CH628623A5 - Process for the preparation of N-aryl-N-(4-piperidinyl)arylacetamides - Google Patents

Description

The invention relates to a process for the preparation of N-aryl-N- (4-piperidinyl) arylacetamides of the formula

. . Ä

■ '- "OC?

(I-b)

N-C-CH "-Ar i '

• ^ Ar in the

L1 an alkyl radical having 1 to 10 carbon atoms, a cycloalkyl, cycloalkyl-lower alkyl or lower alkenyl radical,

Ar is a phenyl group which is optionally substituted by up to two halogen atoms or lower alkyl radicals, a pyridinyl or 2-pyrimidinyl group,

acylated in an inert organic solvent and, provided that Ar1 in the end product of formula Ib represents a mono- or dihydroxyphenyl group, blocks the hydroxyl group or hydroxyl groups with a protective group and, after the end product has been prepared, the protective groups are split off by alkaline hydrolysis and the compounds obtained optionally converted into an acid addition salt by reaction with an inorganic or organic acid.

The reaction according to the invention can be carried out in a customary manner, for example by refluxing and stirring the reactants in an inert organic solvent. Specific examples of solvents which can be used are lower aliphatic alcohols, such as methanol, ethanol, propanol and butanol, aromatic hydrocarbons, such as benzene, toluene and xylene, 5 ketones, such as 4-methyl-2-pentanone, ethers, such as dioxane, glycols such as ethylene glycol, dimethylformamide and nitrobenzene.

If the radical Ar1 in the compounds of the formula I-b e.g. a phenyl group substituted by one or two hydroxyl groups

3rd

628623

means, the hydroxyl groups in the compounds of formula III can preferably be protected by a protective group, such as a lower alkyloxycarbonyl group. The corresponding derivatives of the compounds of the general formula I-b are obtained, from which the protective group can be split off again by alkaline hydrolysis, for example using dilute aqueous alkali metal hydroxide solution.

Specific examples of the acids used to prepare the salts of the compounds of the general formula Ib are hydrohalic acids, such as hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, maleic acid, Hydroxy succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, a-hydroxyphenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid and 4-amino-2-hydroxybenzoic acid. The free bases of the compounds of the general formula I-b can be set free again from the salts.

The starting products, a number of which are known, can be produced as follows:

(Il-b)

Splitting off of P

■ OC

The starting materials of formula VII, in which X represents a hydrogen atom, i.e. the compounds of the general formula VH-a, are usually made from the compounds of the formula

-CK *

NH

f

Ar wherein

P is a protecting group. First, the protecting group P is split off in a manner known per se. The N-aryl-4-aminopiperidines of the formula XI below are obtained. Sois then the L1 substituent is introduced by N-alkylation.

If the radical L1 in the products of the general formula VH-a represents a methyl group, these compounds of the general formula VII-a-1 can be obtained directly by reducing a compound of the general formula II-a, in which P denotes a lower alkoxycarbonyl radical ( II-a-2), with a reducing agent such as lithium aluminum hydride. This reaction is illustrated by the following reaction scheme:

(XI)

NH I

Ar

Introduction of Li

- ■ -OC

Ar

(VII-a)

H

(lower alkylJ-O-ft-N V

\ Ana

(II-a-2) Ar

LSA1H

CH3

-Oh

\ At the

(VII-a-1)

NH

I.

Ar

The intermediates of general formula II in which X represents a 40 by reaction with a basic alkali metal compound such as a lower alkoxycarbonyl group, i.e. the compounds of all-sodium hydroxide, into the metal salt, preferably the sodium salt according to formula II-b, can be prepared as follows: of the general formula XVI. It is not necessary that

1 -Benzyl-4-piperidone of the formula XII is isolated with an arylamine carboxylic acid of the general formula XV or

of the general formula IX and an alkali metal cyanide, for example. The alkali metal salt is obtained directly when the hydrolysis wise potassium cyanide, in an aqueous solution of a carboxylic acid, 45 of the carboxylic acid amide of the general formula XIV with one such as acetic acid, or in an aqueous solution of a lower one ali- alkali metal hydroxide is carried out.

phatic alcohol and in the presence of an equivalent of an anor- The salt of the general formula XVI is then reacted by

ganic acid, such as hydrochloric acid, implemented. In this way, a tongue with a lower haloalkane of the general formula

Nitrile group and an amino group in the 4-position of piperidine-XVII in a solvent such as hexamethylphosphoric acid tri-

introduced around. An intermediate product of the general formamide is obtained in the corresponding benzylpiperidine derivative of the general mei XIII. The nitrii of the general formula XIII is converted to formula II-b-1.

then by treatment with an acid to give the amide of the general The esters of the general formula II-b-1 can also by

Formula XIV hydrolyzed. For this purpose, a concentrated conversion of the carboxylic acid of the general formula XV into the trated aqueous mineral acid, such as hydrochloric acid, phosphoric acid or acid halide of the general formula XVIII, is carried out, for example, by

Sulfuric acid. The amide of general formula XIV 55 treatment with a halogenating agent such as thionyl chloride

is then carried out in a manner known per se for the corresponding carbon and subsequent reaction of the acid halide with a low

acid of the general formula XV hydrolyzed. This can be either ren aliphatic alcohol or by reacting the carboxylic acid with a dilute mineral acid such as hydrochloric acid or sulfur with the alcohol in the presence of an acid. The acid or with a base, such as sodium hydroxide solution or potassium hydroxide solution. The methods described above are reacted by the following

The carboxylic acid of the general formula XV obtained is then explained in the 60 scheme:

QCH2-0 = O + (IX) + KCN CH3COOH / HgO ^

(XII)

628623

o ».- oc

NH I

(XIII) Ar O

ë-NH.

O0B'O:

NH I

(XIV) A *

O

NaOH

o ™

\ / NH

NH

I.

Ar

(XV)

(XVI)

lower haloalkane (XVII)

SOCI.

o II

/ V C-Cl ssnr O -'- OC

Alcohol - * - j

H + «

/ (XVIII) / lower aliphatic,

V

0 "» 0

o (i

alcohol

C-0- (lower alkyl)

(ii-b-i)

The intermediates of the general formula II-b, in which P represents a lower alkoxycarbonyl or benzyloxycarbonyl radical, i.e. the compounds of the general formula II-b-2 can be prepared from the compounds of the general formula II-b-1. First, the benzyl group is usually split off and a lower alkoxycarbonyl or benzyloxycarbonyl radical is introduced into the compound of the general formula XIX obtained in a manner known per se, for example by reaction with a

NH I

Ar

Alkyl haloformate or benzyl halide, or directly by reacting the compounds of the general formula II-b-1 with a lower alkyl halide or benzyl halide. In this way, the benzyl group from the compounds of the general formula II-, b-1 can be replaced by the corresponding lower alkoxycarbonyl or benzyloxycarbonyl group. This process follows the following reaction scheme:

(II-b-1)

H.

Pd-on-C

»Q

U-O- (lower alkyl)

NH I

Ar

(XIX)

I.

(II-b-2)

5

628 623

The starting materials of formula VII, in which X represents a lower alkoxycarbonyl radical, i.e. the compounds of general formula VII-b are preferably prepared by introducing group L1 into an intermediate of general formula XIX in the manner described above.

The compounds of general formula II and VII in which X represents a lower alkoxymethyl radical, i.e. the compounds of the general formulas II-c and VII-c can be prepared as follows:

A lower alkyl ester of the general formula II-b is converted to 4-piperidine-methanol with a reducing agent, such as sodium bis- (2-methoxy-ethoxy) aluminum hydride (Red-Al) in an organic solvent, such as benzene, or with lithium borohydride of the general formula XX reduced. This compound is then treated with an alkylating agent, such as a lower o II

Haloalkane or lower dialkyl sulfate, in an organic solvent, such as benzene, toluene, xylene or tetrahydrofuran, in the presence of a quaternary ammonium salt, such as triethylbenzylammonium chloride. The intermediate of general formula II-c is obtained. The intermediates of the general formula VII-c can be prepared by removing the protective group from the compounds of the general formula II-c and then introducing the radical L1 into the compound of the general formula XXI in the manner described above.

The intermediates of the general formula VII-c can also be prepared by reducing the alkyl ester of the general formula VIII-b to the corresponding 4-piperidine methanol of the general formula XXII and subsequent etherification in the manner described above. These processes are illustrated by the following reaction schemes:

p ^ C-O- (lower alkyl) Red_A1

/ v, CH2OH

NH

I.

Ar

'-t_x

NH I

Ar

(H-b)

(XX)

O-alkylation / - \ CH - 0- (lower alkyl)

> P-N Y

\ / NH

I.

Ar

(II-c)

(II-c)

Splitting off of P

/ \ CH20 (lower alkyl)

HN Y

\ —A

Introduction of L

1

IjJH Ar

(XXI)

•-O;

CH. 0 (not eder alkyl)

IjlH Ar

(VII-c)

O II

/ —V C-0 (lower alkyl)

CX

L-N

Red-Al

NH I

Ar

■ 'O

CH2OH

NH I

Ar

(VII-b)

(XXII)

0-

Alkylation ^

(VII-c)

628623

6

The compounds of formula I-b and their salts with acids are valuable medicinal substances which can be used for the pharmacotherapy of cardiac arrhythmias. This effect was found in experiments on dogs. The experiment is carried out under neuroleptanalge-sie [1 ml / 10 kg body weight fentanyl (0.4 mg / ml) and droperidol (20 mg / ml)]. About 16 hours after the ligament of the posterior descending branch of the left coronary artery, the dogs show multifocal ventricular arrhythmia. The compounds to be examined are given intravenously after a control time of 30 min. The evaluation was based on the following criteria: 0: No effect

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

+ +: Decrease in the number of premature heartbeats and increase in the number of normal heartbeats by at least 50% compared to the control value, -t- + +: normalization of the heart rhythm or decrease in the number of premature heartbeats and increase in the number of normal heartbeats by at least 75% compared to the control value.

The results are summarized in Table I below.

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628623

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Table I- continued

-czh5

4-Cl-C / H. 6 4

Q

-nC3H7

4-Cl-C6H4

• U

-CHj, -ch = ch2

4-Cl-C6H4

-c3h7

2,6- (CH3) 2-C6H3

&

-ìc3ìc7

C6H5

YEAR

• a

C6H5

JD

-iC3H7

4-Cl-C6H4

■ Q

-ic3H7

2,6- (CH3) 2-C6H3

S?

j ^ N

O

C6H5

"iC3H7

6

3-Cl-C6H4

"iC3H7

O

4-Cl-C6H4

-iC3H7

O

3-ch3-c6h4

■ Q

Ù

c6h5

<2

Ù

4-Cl-C6H4

<3

O

3-CH3-C6H4

HCl HCl HCl

(cooh) 2 (cooh) 2

Base HCl

HCl

Base Base

Base (COOH) 2

Base Base

base

++ ++ ++ ++ +++ +++ ++ ++

•• +++ ++ ++ +++ ++

Table 1 - continued

L1

Ar

Ar1

Base or

Antiarrhythmic effects in dogs

Salt form

2.5 mg / kg

5 mg / kg

"iC3H7

0

C «H5

base

+ r

++

"iC3H7

0

0 0

C \

3-Cl-C6H4

base

++

++

"1C3H7

4-Cl-C6H4

base

+

++

-iC.

c

5H7

3-CH.-C.H.

3 6 4

3-C1-C / H-6 4

base

2 HCl. 1/2 HzO

+ ++

++ +++

-c

O

4-Cl-C, H. 6 4

base

+

++

L ^> N

O

3-CH "-C, H, 3 6 4

HOOCCH = CHCOOH

++

+++

.....

Table II

^ -N ~) (X fi

\ / N-C-

CH ^ -Ar

L1

X

Ar1

Base or salt form

Antiarrhythmic effects in dogs

2.5 mg / kg

5 mg / kg

D-

COOCH3

3-Cl-C, H "6 4

Base

+

++

[>

COOC2H5

3-Cl-C6H4

HOOC-CH = CH-COOH

+

++

D-

COOC2H5

4-Cl-C6H4

HOOC-CH-CH-COOH

0

++

O

cooc2h5

3-CH3-C6H4

HOOC-CH-CH-COOH

++

+++

iC3H7

CH2-OCH3

C6H5

HCl

++

++ (+)

11

628623

The examples illustrate the process according to the invention. Parts are by weight unless otherwise specified.

O

II / - \

CH3-CH-0-C-N V = N-Ar

Ar

Kp., ° C / Torr

2-C1-C6H4

160-165 ° C / 0.5-0.6

2,6- (CH3) 2-C6H3

142-145 ° C / 0.01

2-C1,6-CH3 - C6H3

195-200 ° C / 0.2

4-F-C6H4

145-147 ° C / 0.01

3,4- (Cl) 2-C6H3

190-200 ° C / 0.02-0.03

3-CI-C6H4

165-170 ° C / 0.01-0.02

4-Br — C6H4

180-183 ° C / 0.1

2,5- (Cl) 2-CfiH3

-

2-pyridinyl

-

Preparation 1:

A mixture of 52 parts of isopropyl bromide, 19 parts of N- (4-piperidinyl) -3-aminopyridine, 33.3 parts of sodium carbonate, 3 parts of potassium iodide and 720 parts of 4-methyl-2-pentanone is heated under reflux and stirred for 24 h. The reaction mixture is then cooled and filtered. The filtrate is evaporated and the residue is chromatographically purified on silica gel with methanol as the eluent. The pure fractions are collected and the eluate is evaporated. The residue is recrystallized from diisopropyl ether. Yield 1.5 parts of N- [1- (1-methylethyl) -4-piperidinyl] -3-aminopyridine, mp 100.7 ° C.

Preparation 2:

According to preparation 1, but using equivalent amounts of the corresponding bromide and 4- (arylamino) -4-X-piperidine, the following compounds are obtained as free bases or after treatment with hydrochloric acid as hydrochlorides:

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628623

12th

Example 1:

A mixture of 4.5 parts of N- (l-cyclopentyl-4-piperidinyl) -

2-aminopyrimidine, 3.4 parts of 3-methylphenylacetyl chloride and 2 parts of sodium carbonate in 180 parts of xylene are heated under reflux for 17 h and stirred. Then another 9 parts

3-methylphenylacetyl chloride added dropwise. The mixture is then refluxed for a further 67 h and stirred. The reaction mixture is then cooled, water is added and the organic phase is extracted with dilute hydrochloric acid. The aqueous phases are combined, washed with benzene and made alkaline with dilute sodium hydroxide solution with cooling in an ice bath. The product is extracted twice with chloroform. The United

Chloroform extracts are dried, filtered and evaporated. Egg residue is converted into succinate with succinic acid in isopropanol. The salt is filtered off and recrystallized first from ethanol and then from methanol. Yield 1 part of 5 N- (l-cyclopentyl-4-piperidinyl) -N- (2-pyrimidinyl) -3-methylphenyl-acetamide succinate, mp 204.1 ° C.

Example 2:

According to Example 1, but using an equivalent amount of the corresponding N-aryl-4-aminopiperidine and the corresponding arylacetyl chloride, the following compounds are obtained in the form of the free base or after reaction with the corresponding acid as a salt.

l1-0 (

H

N-C-CH_-Ar i z

Ar

(i-b)

l1

Ar

Ar1

Base or salt form

F.

D-

3-pyridinyl c6hs

Fumarate

219.6 "c

O

3-pyridinyl

3-ch3-c6h4

Fumarate

250.3 ° c

D *

2-pyridinyl

3-c1-c6h4

(cooh) 2

205.9 = c

O

2-pyridinyl

3-ch3-c6h4

base

107.8 ° c o

2-pyridinyl

4-c1-c <sh4

base

119.2'c o

2-pyridinyl

2-thienyl

base

129.4-c

D-

2-pyridinyl c6hs

base

108.8: c

D *

2-pyrimidinyl c6h5

(cooh) 2

223.5: c

(ch3) 2-ch-

3-pyridinyl c6h5

base

129.4: c

(ch3) 2-ch -

3-pyridinyl

3-c1-c6h4

base

117.7cc

(ch3) 2- ch -

3-pyridinyl

4-a-c6h4

base

146.6 = c

(ch3) 2-ch-

3-pyridinyl

2-thienyl

base

126.7-c

(ch3) 2 — ch -

3-pyridinyl

3-ch3-c6h4

Base loo ^ c

(ch3) 2 — ch—

2-pyridinyl

3-c1-c6h4

base

102.6 c

(ch3) 2 - ch -

2-pyridinyl

C6Hs

base

72, rc

(ch3) 2 - ch—

2-pyridinyl

4-ci-c6h4

base

83.3 c

(ch3) 2 — ch -

2-pyridinyl

3-ch3-c6h4

(cooh) 2

190.6: c

(ch3) 2-ch-

2-pyridinyl

2-thienyl

(cooh) 2

196.1 c

(ch3) 2— ch -

2-pyrimidinyl

4-ci-c6h4

(cooh) 2

195.7'c

13

628 623

Example S.Em mixture of 5 parts of 1- (1-methylethyl) -4- (phenylamino) -4-piperidinecarboxylic acid methyl ester, 24 parts of 4-chlorophenylacetyl chloride and 4 parts of sodium carbonate in 180 parts of xylene is heated under reflux for 32 h and stirred. The reaction mixture is then cooled, washed with dilute sodium hydroxide solution and extracted with dilute hydrochloric acid. Three layers are obtained. The oil and the aqueous phase are combined and made alkaline with dilute sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The arrears with

Succinic acid is converted into the succinate in isopropanol. The salt is filtered off and recrystallized from a mixture of isopropanol and diisopropyl ether. Yield 5 parts (48% of theory) of 4- [N- (4-chlorophenyl) acetyl-N-phenylamino] -l- (l-methylethyl) -4-piperidinecarboxylic acid methyl ester succinate, melting point 154.2 ° C.

Example 4:

According to Example 3, but using equivalent amounts of the corresponding 4-arylamino-4-piperidinecarboxylic acid ester and the corresponding arylacetyl chloride, the following compounds are obtained in the form of the free base or after reaction with an acid in the form of a salt:

<* X

O

Ë-O-R

l1

Ar1

r

Base or salt form

F.

(CH3) 2-CH-

3-CH3-C6H4

c2h5

(COOH) 2

198.4 ° C

(CH3) 2-CH-

c6h5

c2h5

Fumarate

168.5 ° C

(CH3) 2 — CH—

2-thienyl c2h5

(COOH) 2

156.8 ° C

(CH3) 2 —CH -

4-Cl-C6H4

C2Hs

HCl

191.5 ° C

(CH3) 2-CH-

3-CH3C6H4

ch3

(COOH) 2

170 ° c

(CH3) 2 — CH—

3-C1-C6Hs ch3

(COOH) 2

152.2 ° C

(CH3) 2 — CH—

c6hs ch3

(COOH) 2

165.5 ° C

(CH3) 2 —CH—

2-thienyl ch3

(COOH) 2

173.6 ° C

D-

4-CI - C6H4

c2h5

Fumarate

195.6 ° C

D-

c6h5

c2h5

Fumarate

203.3 ° C

O

3-C1-CsH4

c2h5

Fumarate

207.8 ° C

O

3-CH3-CsH4

c2h5

Fumarate

188.1 ° C

o c6hs ch3

(COOH) 2

197.2 ° C

D-

2-thienyl ch3

(COOH) 2

166.4 ° C

O

3-C1-C6H4

ch3

base

94 ° C

O

3-CH3-C6H4

ch3

(COOH) 2

189.5 ° C

628 623

14

Example 5: and from a mixture of isopropanol and diisopropyl ether

A mixture of 4 parts of l- (l-methylethyl) -N-phenyl crystallized. Yield 2.5 parts of N- [l- (l-methylethyl) -4-piperidinyl] -

4-aminopiperidine, 5.3 parts of sodium carbonate and 180 parts of Ben-N-phenylphenylacetamide hydrochloride of mp 184.4 C.

5 parts of phenylacetyl chloride are added dropwise to zol with stirring. The mixture is then heated under reflux for 15 hours and 5 ^ e'sP'e ^ *> ■ '

touched. The reaction mixture is then cooled, in accordance with Example 5, but using equivalent people with water, aqueous sodium carbonate solution and water, and the appropriate N-aryl-4-aminopiperidine and

washed, dried, filtered and evaporated. The residue of arylacetyl chloride, the following compounds are in the form of a solution of hydrogen chloride in diisopropyl ether and the free base or after reaction with an acid in the form of a

Isopropanol converted into the hydrochloride. The salt is filtered off and 10 salts are obtained.

• '-Oò

N-C-CH, -Ar »^

Ar

(i-b)

l1

Ar

Ar1

Base or salt form f.

(CH3) 2-CH-

c «hs

3-CH3-C6H4

HCl

173.6 ° C

(CH3) 2 — CH—

c6hs

3-Cl-CeH4

HCl

204.8 ° C

(CH3) 2 — CH -

c6h5

2-thienyl

Fumarate

168.1 ° C

CH3

2,6- (CH3) 2-C6H3

C6H5

base

95.5 ° C

ch3

4-CI-C6H4

c6h5

base

1153C

c2h5

4-CI-C6H4

3-OCH3-CaH4

base

90.7 ° C

nC3H7

2,6- (CH3) 2-C "H3

2-thienyl

(COOH) 2

1533C

nC3H7

2,6- (CH3) 2 - C6H3

c6h5

(COOH) 2

16PC

ch2 = ch-ch2

4-a-C6H4

2-thienyl

HCl

227.5 ° C

o c6h5

4-CI-C6H4

base

125.1 ° C

o c6h5

3-CH3-C6H4

Fumarate

161.3CC

[>

c6h5

2-thienyl

base

119 ° C

o c6h5

3-Cl-CsH4

base

121.8'C

o c6h5

c8h5

base

139.8 ° C

D-

3-pyridinyl

4-CI-C6H4

base

149.9 ° C

O

3-pyridinyl

3-C1-C6H4

2 HCH / 2HzO

236.6 ° C

D ■

3-pyridinyl

2-thienyl

base

159.8 ° C

0-

QHS

4-CI-CeH4

HCl

265.8'C

0

c6hs

3-CI-C6H4

HCl

255.4 C.

15

628 623

Example 7:

A suspension of 1.25 parts of sodium amide in 56 parts of benzene is heated to 40 ° C. under nitrogen as a protective gas and stirred. Then a solution of 6 parts of N- (4-chlorophenyl) -

1- (l-methylethyl) -4-aminopiperidine was added dropwise in 56 parts of benzene. After the addition has ended, the mixture is heated under reflux for 16% and stirred. The reaction mixture is then cooled to 25 ° C. and a solution of 7.8 parts of 3,4-dichlorophenyl acetyl chloride in 88 parts of benzene is added. The mixture is then heated under reflux and stirred for a further 2 h, then cooled and mixed with 80 parts of water. The mixture is acidified with dilute hydrochloric acid, the aqueous acid phase is separated off, made alkaline with sodium hydroxide solution and the free base is extracted with chloroform. The chloroform extract is dried, filtered and evaporated. The residue is dissolved in a mixture of 80 parts of diethyl ether and 120 parts of hexane. The solution is left to stand at -10 ° C. for 15 h, some impurities are filtered off and the filtrate is evaporated. The residue obtained is dissolved in 120 parts of diethyl ether, treated with activated carbon, filtered and evaporated. The residue obtained is crystallized from hexane at -10 ° C. Yield 2.2 parts of N- (4-chlorophenyl) -N- [l- (l-methylethyl) -4-piperidinyl] -3,4-dichlorophenylacetamide from

M. 101.7 ° C.

Example 8:

According to Example 7, but using equivalent amounts of the corresponding N-aryl-4-aminopiperidine and the corresponding arylacetyl chloride, the following compounds are obtained in the form of the free base or after reaction with an acid in the form of a salt:

N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] -4-bromo-phenylacetamide, mp 118.1 ° C;

N- (2,6-dimethylphenyl) -N- [l- (l-methylethyl) -4-piperidinyl] -4-chlorophenylacetamide hydrochloride, mp 268.2 ° C;

N- (4-chlorophenyl) -4- (l-methylethyl) -N- [l- (l-methylethyl) -4-piperidinyl] phenylacetamide, mp 104.9 ° C.

Example 9:

5 parts of N- (4-chlorophenyl) -N- [l- (l-methylethyl) -4-piperidinyl] -4-chlorophenylacetamide are dissolved in a mixture of 60 parts of diethyl ether and 16 parts of acetone. The solution obtained is acidified with a saturated solution of hydrogen chloride in isopropanol. The precipitated hydrochloride is filtered off and dried. Yield 7.5 parts of N- (4-chlorophenyl) -N- [l- (l-methyl-ethyl) -4-piperidinyl] -4-chlorophenylacetamide hydrochloride, melting point 266.6 ° C.

Example 10:

From 6 parts of N- [l (l-methylethyl) -4-piperidinyl] -N-phenyl-

2-thiophenacetamide maleate is freed from the base with dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried, filtered and evaporated. The residue is converted into the succinate with a solution of succinic acid in isopropanol. The salt is filtered off and dried. Yield 3.2 parts of mp 167.4 ° C.

Example 11:

The base is set free with sodium bicarbonate from an aqueous solution of 2.8 parts of N- (2,6-dimethyl-phenyl) -N- (1-propyl-4-piperidinyl) -2-thiophenacetamide dihydrochloride and extracted with diethyl ether . The ether extract is dried and evaporated. The oily residue is dissolved in 56 parts of hexane and crystallized at -10 ° C. The crystals are filtered off and dried. Yield 1.6 parts of N- (2,6-dimethyl-phenyl) -N- (1-propyl-4-piperidinyl) -2-thiophenacetamide, melting point 62.5 C.

Example 12:

The base is liberated from 3.9 parts of N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (3-pyridinyl) phenylacetamide maleate with dilute sodium hydroxide solution and extracted with diisopropyl ether. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the succinate with a solution of succinic acid in ethanol. The salt is filtered off and recrystallized from a mixture of ethanol and diisopropyl ether. Yield 3 parts of succinate, mp 192.6 ° C.

Example 13:

A mixture of 50 parts of 4- (phenylamino) -l- (benzyl) -4-piperidinecarboxamide and 600 parts of concentrated hydrochloric acid is heated under reflux for 16 h. After cooling, the reaction mixture is evaporated to 400 parts under reduced pressure. The resulting precipitate is filtered off, washed with water and acetone and dried. Yield 43 parts of 4- (phenylamino) -l- (benzyl) -4-piperidinecarboxylic acid dihydrochloride of melting point 261 to 263 ° C. (dec.).

A mixture of 19 parts of the compound obtained, 14.4 parts of sulfuric acid and 64 parts of ethanol is heated under reflux and stirred for 16 h. The solvent is then decanted. The residue is dissolved in water and the aqueous solution is made alkaline with aqueous ammonia solution and extracted with a mixture of toluene and diisopropyl ether. The extracts are combined, dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of diisopropyl ether and hydrogen chloride gas is passed into the solution. The precipitated hydrochloride is filtered off, washed with isopropanol and dried. Yield 11.5 parts of 4- (phenylamino) -l- (benzyl) -4-piperidinecarboxylic acid ethyl ester dihydrochloride, melting point 212 to 214.4 ° C.

A solution of 101.4 parts of 4- (phenylamino) -l- (benzyl) -4-piperidinecarboxylic acid ethyl ester in 640 parts of anhydrous benzene is added dropwise with refluxing and stirring with 172 parts of a 70 percent solution of sodium bis (2-methoxy-ethoxy ) aluminum hydride in benzene in 160 parts of anhydrous benzene. When the addition is complete, the mixture is stirred at 80 ° C. for a further 2 h. The reaction mixture is then cooled, poured into ice water, made alkaline with sodium hydroxide solution and the product extracted with benzene. The benzene extract is washed twice with water, dried, filtered and evaporated. The residue is converted into the hydrochloride with a solution of hydrogen chloride in isopropanol and diethyl ether. The salt is filtered off, boiled in isopropanol and filtered off after cooling. The salt is boiled up again in acetonitrile and filtered off again after cooling. The base is released in the usual way and extracted with diethyl ether. The ether extract is washed with water, dried and evaporated. Yield 56.6 parts of 4- (phenylamino) -l- (benzyl) -4-piperidinemethanol as an oil.

A solution of 32 parts of the oil in 90 parts of benzene is mixed with 0.2 parts of triethylbenzylammonium chloride and 150 parts of 60 percent sodium hydroxide solution. After vigorous stirring, 10.9 parts of dimethyl sulfate are added dropwise at a temperature below 30 ° C. The mixture is then stirred for 2 Vi h at room temperature and after the addition of a further amount of 2.6 parts of dimethyl sulfate I Vi h. The reaction mixture is then cooled in ice water and 200 parts of water are added. The organic phase is separated off and the aqueous phase is extracted with benzene. The organic phases are combined, washed with water, dried, filtered and evaporated. The residue is purified chromatographically on silica gel with a mixture of chloroform and 3% methanol as eluent saturated with ammonia. The product-containing fractions are collected and evaporated. Yield 24.8 parts of 4- (methoxymethyl) -N-phenyl-1 - (benzyl) -4-aminopiperidine.

5

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15

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35

40

45

50

55

60

65

628623

A mixture of 10 parts of the compound obtained and 200 parts of acetic acid is hydrogenated at normal pressure and room temperature in the presence of 2 parts of a 10% palladium-on-carbon catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water, cooled and made alkaline with aqueous ammonia solution. The product is extracted with chloroform, the chloroform extract washed with water, dried, filtered and evaporated. The oily residue is purified chromatographically on silica gel using a mixture of chloroform and methanol (90:10) saturated with ammonia as the eluent. The product-containing fractions are collected and evaporated. Yield 4.5 parts of 4- (methoxymethyl) -N-phenyl-4-aminopiperidine as an oil.

A mixture of 10 parts of isopropyl bromide, 9 parts of 4- (methoxymethyl) -N-phenyl-4-aminopiperidine, 4.9 parts of triethylamine and 72 parts of dimethylacetamide is heated under reflux for 10 Vi h and stirred. After cooling, the triethylamine hydrobromide formed is filtered off and the filtrate is diluted with water. The product is extracted with toluene, the toluene extract is washed thoroughly with water, dried, filtered and evaporated. The residue is purified chromatographically on silica gel using a mixture of chloroform and methanol (90:10) as the eluent. The product-containing fractions are collected and evaporated. Yield 4.7 parts (42.6% of theory) of 4- (methoxymethyl) -l- (l-methylethyl) -N-phenyl-4-aminopiperidine as an oil.

A mixture of 5.5 parts of the compound obtained in 56 parts of benzene is added dropwise at 26 to 32 ° C. with a solution of 13.8 parts of phenylacetyl chloride in 45 parts of benzene. The mixture is then stirred at 26 to 32 ° C. for 1 h and at 38 to 55 ° C. for a further 3 h and 35 min. After cooling, the precipitated product is filtered off and converted into the hydrochloride in a mixture of isopropanol and acetone (5: 1). The salt is filtered off and dissolved in anhydrous ethanol. After standing at room temperature for 72 hours, the product which has crystallized out is filtered off, washed with a little acetone and dried. Yield 1.05 parts of N- [4- (methoxymethyl) -l- (l-methylethyl) -4-piperidinyl] -N-phenylphenylacetamide hydrochloride, melting point 249.1 ° C.

Preparation 3:

Steps 1 through 4 of Example 13 are repeated. In stage 5, the equivalent amount of the corresponding dialkyl sulfate is used. The following intermediate products are obtained:

4- (methoxymethyl) -N- (3-methylphenyl) -1- (phenylmethyl) -4-aminopiperidine;

4- (methoxymethyl) -N- (4-methylphenyl) -1- (phenylmethyl) -4-aminopiperidine;

4- (methoxymethyl) -N -) (2-methylphenyl) -1 - (phenylmethyl) -4-aminopiperidine;

N- (4-fluorophenyl) -4- (methoxymethyl) -1 - (phenylmethyl) -4-aminopiperidine;

4- (ethoxymethyl) -N-phenyl-1- (phenylmethyl) -4-aminopiperidine;

4- (ethoxymethyl) -N- (4-fluorophenyl) -1 - (phenylmethyl) -4-aminopiperidine.

Preparation 4:

According to step 7 of Example 13 and using equivalent amounts of the corresponding N-aryl-4- (lower alkoxymethyl) -l- (benzyl) -4-aminopiperidine and the corresponding arylacetyl chloride, the following intermediates are prepared:

N- [4- (methoxymethyl) -1 - (phenylmethyl) -4-piperidinyl] -N-phenylphenylacetamide;

N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl] -N- (3-methylphenyl) phenylacetamide;

N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl] -N- (4-methylphenyl) phenylacetamide;

N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl] -N- (2-methylphenyl) phenylacetamide;

N- (4-fluorophenyl) -N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl] phenylacetamide;

N- [4- [ethoxymethyl) -1- (phenylmethyl) -4-piperidinyl] -N-phenylphenylacetamide;

N- [4- (ethoxymethyl) -1- (phenylinethyl) -4-piperidinyl] -N- (4-fluorophenyl) phenylacetamide;

N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl] -N-phe-nyl-4-methylphenylacetamide;

N- [4- (methoxymethyl) -1- (phenylmethyl) -4-piperidinyl] -N-phe-nyl-4-methoxyphenylacetamide;

N- [4- (methoxymethyl) -l- (plienylmethyl) -4-piperidinyl] -N-phe-nyl-2-thiophenacetamide;

Example 14:

According to stage 5 of example 13, the following compounds are prepared from the corresponding benzyl compounds:

N- [4- (methoxymethyl) -4-piperidinyl] -N-phenylphenylacetamide;

N- [4- (methoxymethyl) -4-piperidinyl] -N- (3-methylphenyl) phenyl acetamide;

N- [4- (methoxymethyl) -4-piperidinyl] -N- (4-methylphenyl) phenyl acetamide;

N- [4- (methoxymethyl) -4-piperidinyl] -N- (2-methylphenyl) phenylacetamide;

N- [4- (ethoxymethyl) -4-piperidinyl] -N-phenylphenylacetamide;

N- [4- (ethoxymethyl) -4-piperidinyl] -N- (4-fluorophenyl) phenyl acetamide;

N- [4- (methoxymethyl) -4-piperidinyl] -N-phenyl-4-methylphenyl acetamide;

N- [4- (methoxymethyl) -4-piperidinyl] -N-phenyl-4-methoxy-phenylacetamide;

N- [4- (methoxymethyl) -4-piperidinyl] -N-phenyl-2-thio-phenacetamide.

16

5

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15

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30th

35

40

45

50

Claims (3)

628623 1. Process for the preparation of N-aryl-N- (4-piperidinyl) aryl acetamides of the formula ■ • -oc? (I-b) N-C-CH -Ar i ^ • A arm L1 an alkyl radical with 1 to 10 carbon atoms, a cyclo- alkyl, cycloalkyl-lower alkyl or lower alkenyl radical, Ar is a phenyl group optionally substituted by up to two halogen atoms or lower alkyl radicals, a pyridinyl or 2-pyrimidinyl group, Ar1 is a phenyl group or a thienyl group optionally substituted by up to two halogen atoms, lower alkyl or alkoxy radicals or hydroxyl groups and X is a hydrogen atom, a lower alkoxycarbonyl or Represents alkoxymethyl group, and their acid addition salts with acids, characterized in that a compound of the formula / "V - \ - Ä (VII) NH I. Ar with the corresponding arylacetyl halide of the formula O II Halogen — C — CH2 - Ar1 (III) acylated in an inert organic solvent and, provided that Ar1 in the end product of formula Ib represents a mono- or dihydroxyphenyl group, blocks the hydroxyl group or hydroxyl groups with a protective group and, after the end product has been prepared, the protective groups are split off by alkaline hydrolysis and the compounds obtained, if appropriate, by reaction converted into an acid addition salt with an inorganic or organic acid. 2. The method according to claim 1, characterized in that one carries out the reaction in the presence of a base. 2nd PATENT CLAIMS 3. The method according to claim 1, characterized in that in compounds of formula III mono- or dihydroxyphenyl groups with lower alkyloxycarbonyl radicals are intermediately protected, which can be removed by alkaline hydrolysis. Ar1 represents a phenyl group or a thienyl group which is optionally substituted by up to two halogen atoms, lower alkyl or alkoxy radicals or hydroxyl groups and X represents a hydrogen atom, a lower alkoxycarbonyl or Al-5 koxymethyl group, and their acid addition salts with acids. The alkyl radicals L1 can be unbranched or branched radicals having 1 to 10, preferably 1 to 6, in particular 2 or 3, carbon atoms. Specific examples of these alkyl radicals are the methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, butyl, 2-methylbutyl, 1,1-dimethylethyl, pentyl, hexyl, Heptyl and decyl group. The term lower alkyl or alkoxy radical means unbranched or branched radicals having 1 to 6, preferably 1 to 3, carbon atoms. Specific examples of these radicals are the methyl, 15 ethyl, 2-methylethyl, propyl, butyl, pentyl and hexyl group and the corresponding alkoxy radicals. The lower alkenyl radical can contain 3 to 6 carbon atoms. Specific examples of this residue are the 2-propenyl, 2-butenyl, 3-butenyl and 2-pentenyl groups. The double bond is preferably in the β-slope. The 2-propenyl group is particularly preferred, i.e. the allyl group. The cyclo-alkyl radical can contain 3 to 6 carbon atoms. Specific examples are the cyclopropyl, cyclobutyl, cyclopentyl and cyclo-hexyl group. The cyclopentyl group is preferred. Specific examples of the cycloalkyl-lower alkyl radical are the cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl groups. The cyclopropyl methyl group is preferred. Specific examples of the lower alkoxycarbonyl and alkoxymethyl group are the methoxy and ethoxy compounds. Halogen atoms are fluorine, chlorine, bromine and iodine atoms. The fluorine, chlorine or bromine atom is preferred, in particular the chlorine atom. Specific examples of the compounds of the general formula Ib are N- (4-chlorophenyl) -N- [l- (l-methylethyl) -4-piperidinyl] phenylacetamide, N- (4-chlorophenyl) -N- (l-ethyI- 4-piperidinyl) phenylacetamide and N-phenyl-N- (l-cyclohexyl-35 4-piperidinyl) -3-chlorophenylacetamide and their salts with acids. The salts of the compounds of the general formula I-b can be derived from inorganic or organic acids. The process according to the invention for the preparation of the compounds of the formula I-b is characterized in that a compound of the formula ^ \ f K (VII) NH Ar with the corresponding arylacetyl halide of the formula O II Halogen — C — CH2 - Ar1 (III)