DK153474B - Analogy method for preparation of N-aryl-N-(4-piperidyl)- arylacetamide derivatives - Google Patents

Description

DK 153474B

The present invention relates to an analogous process for the preparation of novel N-aryl-N- (4-piperidyl) -arylacetamides having the general formula (I) set forth in the preamble of claim 1, or pharmaceutically acceptable acid addition salts thereof, which process is peculiar to the characterizing part of claim 1. The present compounds are useful as anti arrhythmic agents.

Some N-aryl-N- (4-piperidyl) amides are known in the art which have analgesic activity. A number of such compounds 10 can be found in the following references: U.S. Patent No. 3,164,600 and C.A., 77, 34349a (1972).

The antiarrhythmic compounds prepared by the process of the present invention differ from such known compounds as to the nature of the arylacetamide group associated with the 4-position of the piperidine nucleus.

DK 153474 B

2

It is further known from U.S. 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 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 is N- (1- [2- (3-indoyl) ethyl] -4-piperidyl) propio-nanilide is devoid of antiarrhythmic activity.

In the process of the invention, the novel N-aryl-N- (4-piperidyl) arylacetamides of the general formula are prepared: 15 y <X i, \ _ / XN-C-CH-Ar

Ar or pharmaceutically acceptable acid addition salts thereof, wherein: L · 1 represents (C --C C q) alkyl, (Cg-Cgj cycloalkyl, (C3-C6) cycloalkyl (C1-C6) alkyl or (C ^-Cg) ) 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 1 represents phenyl, mono- or di-substituted phenyl 20 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 Cg) alkyloxy, X represents hydrogen, (C ^-Cgjalkalkyloxycarbonyl or ((C ^-Cg) alkyloxymethyl, provided that L · 1 is different from (C,-Cg) cycloalkyl when Ar and Ar1 are both phenyl or substituted phenyl and X is hydrogen.

3

DK 153474B

More particularly, in the definition of L · 1, the term "(C 1 -C 4) alkyl" means straight or branched saturated hydrocarbon radicals having 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, decyl; the term (C 1 -C 6) alkyl or "lower alkyl" used in the foregoing and in the following definitions means straight or branched chain alkyl radicals having from 1 to 6 carbon atoms, e.g. methyl, ethyl, 2-methylethyl, propyl, butyl, pentyl, hexyl; 10 "(C 6 -C 6) alkenyl" means alkenyl radicals having from 3 to 6 carbon atoms such as e.g. 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl; the term "(C 3 -C 6) cycloalkyl" means cyclic hydrocarbon radicals having from 3 to 6 carbon atoms, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and the term "halogen" 15 is common to atomic halogens less than 127, i.e. fluorine, chlorine, bromine and iodine.

Starting materials of the general formula (IV) can generally be prepared from a piperidine derivative having the general formula (II) wherein Ar is as previously defined, X 20 is hydrogen or (C 1 -C 8alkyloxymethyl, and Z is (C 1 C 1-6 alkoxycarbonyl, by acylating (II) with a suitable aryl acetyl halide having the general formula (III), preferably chlorinated In process a) of the invention, the protecting group Z of the compound thus obtained is eliminated (IV) by acid or basic hydrolysis to prepare a compound of formula (Ia), which compound is then N-alkylated to prepare a compound of formula (I)

X1 O

30 / \ /, j! in acylation Z-N Y + halogen-C-Cl 2 -Ar _____ ^^ - 'nh

Ar (II) (III) 4

DK 153474B

05 ο ^ ιΐ elimination of ^ \ j-C-CH ~ -Ar1, "^^ protective group (IV) 10" X1- V ° 15 HN \ A a 1 \ - / N-C-CH ^ -Ar (I_a)

Ar 20

The acylation of (II) with (III) can be carried out according to 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.

Elimination of the protective group Z can be carried out using a strong mineral acid, e.g. hydrochloric acid, hydrogen bromic acid or sulfuric acid, or using alcoholic base, e.g. potassium hydroxide in 2-propanol.

The N-alkylation is carried out by reacting (Ia) with a suitable reactive ester having the general formula L 1 -Y, (V) wherein L 1 is as defined above and Y is a suitable reactive ester radical which is .g. halogen, or a sulfonyl radical such as methanesulfonyl or 4-methylbenzenesulfonyl. This reaction may be carried out in the usual manner, e.g. with stirring 5

DK 153474B

and heating under reflux of the reactants together in a suitable reaction-inert organic solvent, such as e.g. a lower alkanol, e.g. methanol, ethanol, propanol or 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.

Process b) for the preparation of the compounds of formula (I) consists of acylating an appropriate N-aryl-1- L1-4-piperidinamine having the general formula (VII) with an appropriate aryl acetyl halide having the formula (III), following well-known N-acylation processes previously described herein for the preparation of (IV) from (II) and (III).

L1- ^ V + (III) _v (I)

NH

Ar 25 (VII) 30 35

6 DK 153474B

When Ar 1 in compounds (L) 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 05 (III) with a suitable protecting group such as lower alkyloxy group. carbonyl, whereby a corresponding derivative (Ib) is obtained, from which the protecting group is easily 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. inorganic acid such as haloacetic acid, e.g. hydrochloric or hydrochloric, sulfuric, nitric or phosphoric; 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, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzoic acid, 4-methylbenzoic acid, 4-methylbenzoic acid, amino-2-hydroxybenzoic acid. Conversely, the salt form can be converted by treatment with alkali to the free base form.

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 hydrogen is (II-a) are conveniently obtained as follows. A 4-piperidinone having the formula (VIII) wherein in the 1-position is an appropriate protecting group Z is subjected to a condensation reaction with an appropriate 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 by a suitable reducing agent, such as e.g. sodium borohydride, or by catalyst

7 DK 153474B

r * lytic hydrogenation using e.g. platinum oxide catalyst to give the corresponding N-aryl-4-piperidine amine (II-a).

The above reactions are illustrated more clearly in the following 05 schematic arrangement: Z'-N ^^ = Q + I ^ N-Ar _ ^ Z -N ^ = N ~ Ar (VIII) (IX) (X)

NaBHd --- y (II-a) Intermediates of the general formula (VII), wherein X is hydrogen, (II-a), are conveniently prepared from (II-a) by first eliminating the protecting group Z in the usual way to obtain an N-aryl-4-piperidinamine having the formula (XI), and then introducing the L 2 substituent as previously described for the preparation of (Ib) from (Ia).

When in the intermediates (Vll-a) a methyl group, (VII-a-1), can be obtained directly by reduction of an intermediate (Ιϊ-a) wherein Zer.en (C C-Cg ') alkoxycarbonyl group, (II-a-2), with a suitable reducing agent such as e.g. lithium aluminum hydride.

25 These reactions are illustrated in the following schematic arrangement: H ^ _ pj

(II- a) Elimination \ HN / \ introduction 1 -N

of Z ^ 'S- / y11 of L1 -' NH

Ar ir (XI) (Vll-a) 8

DK 153474B

(C.-C ^ X-o-L.Ql CH3-0 {h

Ar Ar (II-a-2) (VII-a-1)

Intermediates of general formula (II) wherein χΐ means (C1-C6) alkoxymethyl (II-c), and intermediates of general formula (VII) wherein X means () alkoxymethyl (VII-c) and (C1-C6) ) alkoxycarbonyl, (VII-b) can be prepared as follows: 1-phenylmethyl-4-piperidinone (XII) is reacted with an appropriate arylamine (IX) 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 to form an intermediate product. with the general formula (XIII).

The nitrile (XIII) is converted to the amide (XIV) 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 (XIV) is further hydrolyzed to obtain the corresponding carboxylic acid (XV) using well known amide-to-acid hydrolysis procedures, e.g. in the treatment of (XIV) with a dilute strong acid, e.g. hydrochloric or sulfuric acid, or by alkaline hydrolysis using a suitable base, e.g. sodium or potassium hydroxide. The thus obtained carboxylic acid (XV) is again converted to a metal salt thereof, preferably the sodium salt (XVI), by reaction with base, e.g. with sodium hydroxide. The carboxylic acid (XV) need not necessarily be isolated or purified, but can be used as a crude mixture for the preparation of (XVI) or the salt can be obtained directly when alkaline hydrolysis is carried out.

9 -

DK 153474B

The salt (XVI) is then converted to the corresponding ester (II-b) wherein Z means phenylmethyl, (II-b-1) by reaction with a suitable halogen-lower alkane (XVII) in a suitable solvent, such as e.g. hexamethylphosphorotriamide.

Alternatively, the esters (II-b-1) can be prepared By converting the acid (XV) to an acyl halide (XVIII) in the usual manner by treatment with a suitable halogenating agent, e.g. with sulfinyl chloride, and reacting this acyl halide with a suitable low alcohol or simply by reacting the acid with 10 suitable alcohol in the presence of an acid.

The above reactions are illustrated more clearly in the following schematic presentation:

DK 153474 B

O / \ CH-COOH

CH2-N \ = o + (ix) + KCN -L_-

(XII) I

^ .CH ^ ni-cril-to-amide hydrolysis

Ar (XIII)

ISLAND

aCH -N amide-to-acid hydrolysis 2 \ NH:>

Year

(XIV) O.

QCH2-Q (g-0H

V = 7 \ _ / NH

NaOH / Ar \ SOCl_ / <XV> \ 0 low-

\ = / \ - / NH alkanol V = / ώ \ / 'NH

Ar H * Ar (XVI) \ / (XVIII) halo * n-lower alkane / lower alkanol (XVII)

It a / -V C-O- lava Iky 1 __ Ar (II-b-1) 11

DK 153474B

The intermediates of the general formula (ΙΙ-b), where Z is (C--C)) alkoxycarbonyl, (II-b-2), are then derived from (II-b-1) by elimination of the protective phenylmethyl group and then introduction into the compound (XIX) 05 thus obtained of the (C ^-Cg) alkoxycarbonyl group according to well known methods, e.g. by reaction of (XIX) with a suitable (C 1 -C 6) alkyl halo formate, or directly by reacting (II-b-1) with a (C 1 -Cg) alkyl halogen formate, upon which the phenylmethyl group of (II-b-1) ) is replaced by the desired (C ^-CgJalkoxycarbonyl group).

10 0

II

α-C O-CC-Cg alkyl.

NH

N. Ar \ (XIX) halogen halogens 1 "1 ^ \ formate 20 N. Ψ ^ (II-b-2)

Intermediates of the general formula (VII), wherein X is (C 1 -C 6) alkoxycarbonyl, (V III-b), are conveniently prepared by introducing the L 2 group into an intermediate (XIX) according to the procedures described herein.

The intermediates of the general formulas (II) and (VII) wherein X is (C 1 -C 6) alkoxymethyl, respectively (II-c) and (VII-c) are prepared from the corresponding (C 1 -C 6) alkyl ester of the formula 30 (ΙΙ-b) which is reduced by a suitable reducing agent, e.g. sodium dihydro-bis (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 having the formula (XX). The compound (XX) is then subjected to an O-alkylation reaction with a suitable alkylating agent.

The O-alkylation step can be carried out by reacting (XX) with a suitable halo-lower alkane or a suitable divalkyl sulfate in 12

DK 153474B

an appropriate reducing agent such as e.g. sodium dihydro-bis-ψ (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 having the formula (XX). The pre-05 linker (XX) is then subjected to an O-alkylation reaction with a suitable alkylating agent. The O-alkylation step can be carried out by reacting (XX) with a suitable halo-lower alkane or a suitable dilavalkyl sulfate in a suitable organic solvent, 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 desired intermediate (II-c). The intermediates (VII-c) can be prepared by first eliminating the protecting group in (II-c) and then introducing the L 2 substituent into the intermediate thus obtained (XXI) according to the methods previously described herein.

Furthermore, the intermediates (VII-c) can be otherwise prepared by reducing an appropriate alkyl ester of formula (VII-b) to the corresponding 4-piperidine methanol (XXII) in a similar manner as previously described for the preparation of (XX) from (II-b), and then subjecting (XXII) to an O-alkylation reaction with a suitable low alkyl alkylating agent according to the methods described for the preparation of (II-c) from (XX).

^ The above procedures are illustrated below.

13 DK 153474 B

island

/ - \ C-O- (lower alkyl), CH, OH

"Qy ^^ - CXr

Ar Ar (Π-b). (XX) O-alkyl. is ing / y CH 2 - O- (lower alkyl) - = -> 2-N Y 2

\ - / NH

Ar (H-c) / -v CH O (lower alkyl) (II-c) elimination HN Y 2 introduction of '~ \' NH 71 ^

by Z I L

Ar (XXI). / \ CH O (low alkyl) L -N Y \ _Λνη

Ar (VII-c)

ISLAND

τ 1 / γ0_0 (lavalky1 ^ Ked-Al L1 / γ0112011

\ _ / NH ^ \ _ / NH

Ar Ar (VII-b) (XXII) O-alkyl ring (vn_c j

14 DK 153474B

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 (i.e., N-phenyl-N- [1- (2- (phenylethyl) -4-piperidinyl) propanamide) (0.4 mg / ml) and droperidol ( i.e. 1- {1- [4- (4-fluorophenyl) -4-oxobutyl] -1,2,3,6-tetrahydro-4-pyridinyl] -1,3-dihydro-2H-benzimidazol-2-one ( 20 mg / ml)).

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

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).

DK 153474B

r * ---: --.-,

live in

O) + + + + + -,, I

* s £ t ί i i i i i i i 1 i; g * i £ 'H ω! !

n -Η ω> + + ittoot + + + J

ri _g- S ++ ++ +.

ri * «i <> N! _I __- ___— 4

u I

H

, _j g I

H. ^ Rt ^ OUUOUO Cd cU y, * J) £ .2eeeeeee · ° · ° κ · <1 ω η »cd cd}

jjT5 m M__ I

0!

1 I

ο = υ;

i u I

^ m m m m m m m m m in m m j> <-H E E E E E E E E x x ® ί

II Λ vOvOvOvOvOvOsDO O?>.?> I

II <ο υ υουυυυ υυυ |

S I

^ __ i

rj <τ} <τ} <-Φ -Φ ^ I

e e e e e e e e e k ^ K. i „υυυυυυυυ y ^ oo; <: 1 r; ri! υυυυυ υυυ hoo *

I I I I I I I c 1 1 I

^ m m i __ - ----- 1 m 1 S i

# I

Η H r- Ø 'r Λ ^ v r- Γ— C— t - -

J J * 0 E E E ^ „w V> E E E I

ri, fn E m Vn ^ 1, SP v <n m m i g E cm υ υ o ΚΛ υ * υ υ υ <υ υ c is c υ-ο ts υ ·? ·? ·?

g C I I »<» »1_1 1 1 J

DK 153474B

16 »(

ω J

ί

Ό µ ++ ++ + Η * + I

· * Sc + + + + + + + + + «+ + + +« i 1 m3q + j-4- + + + + + + + + + + + i • H Si i β «« i + J -H ........... ...... ............... '"" "-------------- 1 ---

> 1 <50 I

Si tn X i M G \ i

Ή Ή to I

+ i + i + + ί ϊ i * + Γί ί ί I

+ J h m 1

β · Η κ I

«> Μ; -—---_____ - -i— '- (u; S · ί

SgrtS £ S S S GoS S oEj "" oE3G! <1) + *

m η I

<d (d I

I to I

------—---- "I

ro 'w ** ί XKX n E j0 J ° VXX x - u 6 ° ϋ υ υ ou to mx υ v V ί <t Λ Λ Λ τ n ffi Ευ rt sT rt in' aT sT '<huo U tnuuou υ K ^ ^, ^ (ΜΓΟ ^ ΓΟ ^ ΓΟ'φΓΟ ^ υ ^ ΟυΟ ^ i

__ I

M ro lO sT »T & Γ« 'CO CO CO W vO .Γ »t E E E ^ ϋ *

vO vO vO U - 1 --- Sj I

"Never! + · Φ · + + ^ ^ 'i4, + t i i + r <- E ^: KEEEEEEEE «I. vO vØ Ό sO \ D vD vO vO vO i ί-C i« 2 υουυυυυϋϋουυγυνοϋ «

% I I I l I I I I l v_ ^ v-- V ^ 'v_ ^ I

__f I — I · —f H · —I Η Η Η Η I I l l Η I | uOUOUUOUONO'tf'tfCQNOO'-Ø t

Jlllllllt »« «· * (“ I

- ^ ^ τί -ψ'φ'φ'Φ'Φ '^ ^ ΜΓΟίΟ'Φηΐ ηΐ. i f k5 s ί s s k k k s s k x e x e x x; CO ΓΟ ro ro ro rorororororotororororo υ υ υυυυυυυυυυυυου; «-I .r + · Μ * M · Η · γΗ .r + · * Η ·« * ** “* **" * * »“ * * M '7 * 7' 7 | I i III iii »I» r III i_! 17

DK 153474B

«3 W) 1 I <^ bp ++ H- +

ljp + -I- + + + + I

^^ + + + + + + • H OJ ^ BO -: - • P C J..

> 10 5 ° island-c µ ω, io'H S +++ H- • Ηδΐή ++++ ++ ++ j c G * H (s) (d c

M

H ^

, -! S <U 4J GJ <D «U

Q) M wcnmtn »S n O ri nj tf ri ri O U

I £ j j, σ .Q 43 .Q 43 O a

(D 4J · U

W H ^

rd id Λ W

"Φ tf" tf W 'tf

ffi ffi r ^ ° K

• tf vO sO sO

- X o Ό · υ P VO I I · <* Π ro ro W ro

i ΪΠ ffi U »n m S

tp o υ o K a υ 1 1 11, r i ° 1 • tf ro tf ro u U to to to a a

vO vO

υ υ

I I

tf tf tf ”tf 03 03 a a a a to to so vO vO vO tu a * υ ο υ υ g o <1 till» - <* - * in ♦ —I t-H * - (I I fy4 υ υ υ υ ο ο

tf tf tf tf tf {S3 {S3 U

_ | fv, m m m m m m a a a a a a a m 03 f \ J (M 03 03 n (s υ υ υ υ υ c a

I I I I I I I I

DK 153474B

lo ._, -, - '- - "......- ......" ..... 1 χ

9 I

l

fco I

rH H * + * t * + I

from μ + + -t- + +, + + +. + + + + + I

+ + + + + 1 + + + '+ + + + +,

ΗΛ C J

H m li | r_r ----. | £ 1¾ + i .2ίε ο + ° ί + + + + ί + · + + + + + i • p u m;

C · Η · »I I

• all> not,

I I

CM c \ l j r · »μ η η n w Π 05 01 O m w w 1 i — i ΕΕΕΟΟηΚΚ, ο, α.ογ, ο, ο.ο i H E? U ϋ O «Φ M v_ ^ w - i O« i m i

<D 4J I

CO * - [I.

<0 ns I

Λ CO ___________i

tf 'tf J

• ψ t} <E <tf S i

«Q 3 D1 3 13 333« i i l · «. f l · I

K u u u E U U i

vO I I I vO I I I

O ro «tf co U tf ro i

........ '- - - "I I

ro ro 1 e e

vO o I

υ υ i

I I I

tf Tf -tf Is3 'tf. *

^ Kffiffico E ro. ^ £ - = £ · = ν% - = \ I

<VO VO VO Ό te, K)! υ υ υ o υ υ <v /) “V_y ^ / Yj / Vy«

'' 'Y m m J, -r-' i-y - I

u υ u J> E E o J)! i i i,> ° i * i • tf-tf-tftvaUU notfcvi i i

--- 1 -—- "-—- I

cvj I

rr> I

υ! ά ί Η Ο I— r— ['-t'-t'-t'-r'-t ^ 1 te' n E 'E E te E E E E E! I te ro ro co, - | ro ro ro ro ro ro, -i.-1 i-1.

f.1 * j {ί Ψ i t ^ i i ΐ W3;

is DK 153474 B

bO Φ X Ό ^ v c Μ. i “^ 6 + + + + + + + t βΧ + + + + + + + + S in +

-P -H

> i__ • f 2 bO --- P 'C M -H <(0 C to + + + + + + + · + β 1h in + *> (sT' O '"-: - M 1 ~ n

HH HH

Λ; island

n O

> u M „<y 4) 4) v fi 1) in 1 to cn m t n. »

H ri ri 'ri ri · ri Y

J6fl Λ “g” i Γ ”o X o g v Ϊ · n o 8

CO Ή O U

ri ri O.

Λ to χ

Tf Tf '

Tf Tf K Tf Tf W Tf X ffi 1> X X s

υ u o υ V

- m J, J, k J, Λ X £% £ o o o o o o g

<.nO i i i i i i i V

About Tf m co Tf co (ή

t- r- γη x x X X

_g

DK 153474B

20 bO + * s «+ ~ h & + + + + + Φ c ++ ++ ++ c (li Ci ^

• H .G

g ---- -P -A> 1

g S 'M

HG i /

H -A

(d G above • H c,, jj u C ++ + + + ° + + <d>

M

X X E

O O O

O O O

υ o υ „a a i h g υ υ υ ^ ^ -3 ii II il δ η ε - ° χ χ χ a«% ο υ υ

Ρ III

υ υ υ 7 S η ο ο ο rsj id id ΟΟΟ

53 Λ ω fi X X

Ο 0 = V / = \ *> Æ) «* ffi ffi 53 ti ° m I J" V NO vO vo V * r £ O O O * o / <S Λ Z χ u

A- O O O O

I I I I

ro ro ro

rO

m in m jr «53 53 53 υ X m cm ni / -λ .0 0 0 0 7 y O O O O r \ j

O O O O X

O O O O O

å ^ όώόό ΰ "ra · η <

Bt 21

DK 153474B

The following examples serve to illustrate the invention. Unless otherwise indicated, all parts therein are parts by weight.

MANUFACTURING OF OUTPUT MATERIALS.

Example 1.

05 A mixture of 19 parts of 1- (phenylmethyl) -4-piperidinone, 11.8 parts of 3-pyridinamine, 120 parts of methylberizen 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 separation of the calculated amount of water, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,21-oxybispropane and evaporated again 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) -4-15 piperidinylidene] -3-pyridinamine in 40 parts of ethanol is added portions of 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 uptake of the calculated amount of hydrogen, 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 22nd

DK 153474B

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, mp 127 - 129 ° C.

Example 2.

A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 05 159.5 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 3

Repeating the procedure of Example 2 and using an equivalent amount of a suitable arylamine instead of the 4-chlorobenzeneamine used therein, the following compounds are obtained: 0 II / - \ - CH 3 -CH 2 -O-CN V = -N -Year

Ar boiling point at specified pressure 2-Cl-C ^ H 160-165 ° C / 0.5-0.6 mm 6 4 2.6- (CH ~) -C_H0 142-145 ° C / 0.01 mm

OL · O O

2-Cl, 6-CH3-C6H3 195-200 ° C / 0.2 mm 23

DK 153474 B

Ar boiling point at specified pressure 4-F-CgH ^ 145-147 ° C / 0.01 mm 3.4- (Cl) 2-C6H3 190-200 ° C / 0.02-0.03 mm 3- Cl-C6H4 165- 170 ° C / 0.01-0.02 mm 4- Br-C ,, H. 180-183 ° C / 0.1 mm 6 4 2.5- (Cl) 2-C6H3 2-pyridinyl

Example 4

A mixture of 171 parts of ethyl 4-oxo-1-piperidine carboxylate, 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 5

A mixture of 34 parts of ethyl 4-oxo-1-piperidinecarboxylate, 10 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 6

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 regular

DK 153474B

The 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 05 parts of ethyl 4 - [(4-chlorophenyl) amino] -1-piperidinecarboxylate, mp 115-118 ° C.

Example 7

Following the procedure of Example 6 and using an equivalent amount of a suitable ethyl 4-arylimino-1-piperidine-10-carboxylate, the following compounds are prepared:

ISLAND

II r - \ / H

W 'nh

Year

Ar melting point / boiling point

2-Cl-CgH 4 m.p. 89-93 ° C

2- C1,6-CH3-C6H3 m.p. 99.5 ° C

4-F-C6H4 kp. 140-142 ° C / 0.01 mm

3.4- (Cl) 2-C6H3 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-C6H3 m.p. 107.2-110.3 ° C

2-Pyrimidinyl Example 8.

To a stirred and refluxed mixture of

DK 153474B

250 parts of ethyl 4 - [(2,6-dichlorophenyl) imino] -1-piperidine carboxylate in 160 parts of methanol and 160 parts of 2-propanol are 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 - [(2,6-dichlorophenyl) amino] -1-piperidinecarboxylate, m.p. 107.2 - 116.6 ° C.

Example 9

A mixture of 45 parts of ethyl 4 - [(2,6-dimethylphenyl) imino] -1-piperidine carboxylate, 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, m.p. 195.5 ° C.

A mixture of 10 parts of ethyl 4 - [(2,6-dimethylphenyl) amino] -1-piperidinecarboxylate and 135 parts of hydrogen bromic acid solution 25 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 30 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

DK 153474 B

26 absolute ethanol and 2-propanone one after the other and dried to give 13 parts of N- (2,6-dimethylphenyl) -piperidinamine / dihydrobromide, mp 300 ° C.

Example 10.

To a stirred and cooled (ice bath) mixture of 165 parts of ethyl-05 4- (2-pyridylimino) -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 2,21-oxybispropane. The salt is filtered off, washed with 2,2'-oxybispropane and dried in vacuo to give 38 parts of ethyl 4- (2-pyridylamino) -1-piperidinecarboxylate.

Oxalate.

A mixture of 90 parts of ethyl 4- (2-pyridylamino) -1-piperidinecarboxylate, 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 11.

A mixture of 7 parts of ethyl 4- (2-pyrimidylamino) -1-piperidinecarboxylate and 120 parts of hydrogen bromic acid solution 48% is stirred 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 regular

27 DK 153474 B

the 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 de. le N- (4-piperidyl) -2-pyrimidinamine / dihydrochloride / hemihydrate, m.p. 268/5 ° C.

Example 12.

A mixture of 32/5 parts of methyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of 10 palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The oily residue solidifies by scraping in 2,2'-oxybispropane. The product is filtered off and dried in vacuo to give 20 parts (85%) of methyl 4- (phenylamino) -4-piperidinecarboxylate / mp 139.1 ° C.

Example 13.

To a stirred solution of 58 parts of ethyl 4 - [(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 of this, the whole is 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 14.

Following the procedure of Example 13 and using equivalent amounts of a suitable ethyl 4-aryl amino-1-piperidinecarboxylate and a suitable arylacetyl chloride, respectively, in place of the ethyl 4 - [(4-chlorophenyl) amino] used therein. -piperidine carboxylate and benzene acetyl chloride are prepared as follows.

DK 153474 B

Searching compounds: «> γH o CH, -CH - O-C-N X II, \ _ / 'N-C-CH.-Ar I 2

Year

Ar ’Ar ^ melting point

2,6- (CH3) 2-C6H3 2-thienyl 94.5 ° C

4-Cl-CgH 4 2-thienyl 98.5 ° C

4-C1-C6H4 4-C1-C6H4 127.5 ° C

4-C1-C6H4 4-CH3-C6H4 112.5 ° C

2-C1-C6H4 C6H5 123.0 ° C

2- Cl, 6-CH3-C6H3 C6H5 114.5 C

4-F-CgH 4 CgHg 82.0 C

3.4- (Cl) 2-C6H3 C6H5 115.0 ° C

3- Cl-CgH4 C6H5. 92.0 ° C

4- Cl-CgH 4 4-F-CgH 4 109.0 ° C

4-Cl-CgH4 3-CH3-CgH4 121.5 ° C

4-Br-CgH4 CgH5 114'5 ° C

4-Cl-CgH4 3-OCH3-CgH4 121.2 C

4-Cl-CgH4 2-Cl-CgH4 139.3 ° C

4-C1-C6H4 3-C1-C6H4 142.7 ° C

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) 2-CgH3 4-Cl-CgH4 136.9 ° C

2.5- (Cl) 2-CgH3 4-Cl-CgH4 107.0 ° C

2.6- (Cl) 2-CgH3 4-Cl-CgH4 140.0 ° C

v 29

DK 153474B

Example 15

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 05 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-10-bisethane to give 5 parts of ethyl 4- [N- (2,6-dimethylphenyl) - N- (phenylacetyl) amino] -1 -piperidine carboxylate, m.p. 106 ° C.

Example 16.

To a stirred solution of 15 parts of ethyl 4 - [(4-chlorophenyl) amino] -1-piperidinecarboxylate, 5.4 parts of N, N-diethylethanamine and 160 parts of benzene is added dropwise 11.07 parts of 4-methoxy-benzeneacetyl. - 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 1,11-oxybisethane and 40 parts of hexane. The crude solid product is filtered off and recrystallized from a mixture of benzene and 1,11-oxybisethane to give 3 parts of ethyl 4- 4- N- (4-chloro-phenyl) -N - [(4-methoxyphenyl) acetyl] amino} -1-piperidinecarboxylate, m.p. 137 ° C.

Example 17

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.

30

DK 153474B

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 135-10 140 ° C at 0.2 rm pressure) and the distillate is crystallized from petroleum ether to give 21 parts of 1- (1-methylethyl) -N-phenyl-4-piperidinamine, m.p. 69.3 ° C -

Example 18

A mixture of 52 parts of 2-bromopropane, 19 parts of N- (4-piperidyl) -3-pyridinamine, 33.3 parts of sodium carbonate, 3 parts of 15 potassium iodide and 720 parts of 4-methyl-2-pentanone is stirred and kept under reflux for a period of time. 24 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-piperidyl] -3-pyridinamine, m.p. 100.7 ° C.

Example 1.9 *

Following the procedure of Example 25 and using 25 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 listed, the following compounds are obtained in free base form or after treatment with hydrochloric acid in hydrochloride salt form: 31

DK 153474 B

rn- 1 '

rH r- (γΊ r — I

H ° ° O

s O.

_Q____ υ υ o o υ υ r. Υ * 00 000 O ^ o S * vot-Uf- · ^^ me co Κ ^^, ο r *> ·. g ~ O · * 81 co co "i1 ro in m co in o rf v £ i co ^ o σ 'O' \ y m

r— <* - (r-H t-4 r-i t-1 CM

~ w ““

ISLAND

Ή

4J O

H CM

«J K

»O .. N ^

M N- <^ CJd) V <U

Φ * —1 (/) 05 cn tø • H "!, - |. — Τ 'ri ri 1—1 · —I r ~ A (0 njr- ^^ uu ^ - ^ ouu ^^ o? S k k k a w

$ CM CM CM CM CM CM CM

CO

XI

in m tn m iE co

cm E cm K

υ υ υ o - ^ χΟΟΧΧΟΟΧΧΧΧ Λ o o o o »C I-3 -ϋ_ϊ -„ - Λ 3 °. % t.% ^ h «£ S nf µ m ra x) * d

<f · Η * J * U

m m t * m m m "^ in

XX £ £ K K £ & ^ E

vO vO i i vO Ό Ό i „Ό

UUcocmUUUcmcmU

II · * XX,,,,, X in.

>> ώώόόό >> ώ

H, CO "" CO CO CO

4 K K XX

υ υ υ_ _υ

V

32

DK 153474B

Example -20

To a stirred mixture of 15 parts of N- (4-chlorophenyl) -4-piperidinamine, 12 parts of Ν, Ν-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 05 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-10 (4-chlorophenyl) -1- (2-propenyl) -4-piperidinamine, m.p. 90 ° C.

Example 21

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 is added dropwise to a solution of 5.1 parts 1-iodopropane in 80 parts 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 22

To 0.5 parts of a solution of 2 parts of thiphene in 40 parts of ethanol are added 2 parts of cyclopentanone, 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 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.

All. washed twice with dilute sodium hydroxide solution, dried, filtered and evaporated. The residue is crystallized out 33

DK 153474B

from 2,21-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 23 05 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 uptake of the calculated amount of hydrogen 10, 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 24

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 1,1'-oxybisethane.

After the addition is complete, stirring and heating are continued under reflux 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 25 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.

MANUFACTURING OF FINAL PRODUCTS

Example 25 (First Step of Method a)

A mixture of 20 parts of ethyl 4- [N- (2-chlorophenyl) -N-30 (phenylacetyl) amino] -1-piperidinecarboxylate and 300 parts of hydrogen bromic 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 is added water and sodium chloride.

DK 153474B

34 hydroxide solution in succession. 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 26 (First Step of Method a)

Following the procedure of Example 25 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: O

Year

Ar Ar1 melting point

2- Clf6-CH3-C6H3 CgH5 157 ° C

4-F-CgH4 CgH5 96.5 ° C

3.4- (Cl) 2-CgH3 CgH5 81 ° C

3- Cl-CcH. C-H ,. 110.5 ° C

6 4 above

4- C1-C..H. 4-F-C ^ H. 109 ° C

6 4 6 4

4-C1-C-H, 3-CH - C-H. 104.5 ° C

6 4 3 6 4

4-Br-C-H. C-Hc 121.5 C

6 4 6 5

4-Cl-CgH4 2-Cl-CgH4 72.9 C

4-C1-C-H. 3-C1-C-H. 64 ° C

6 4 6 4

2-Cl, 6-CH 3 -CgH 3 4-Cl-CgH 4 120.7 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

35

DK 153474B

Example 73 (First step of procedure a) ψ

A mixture of 5 parts of ethyl 4- [N- (2,6-dimethylphenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate in 60 parts of hydrobromic acid solution 48% is heated until the evolution of carbon-05 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 28. (First Step of Method a)

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

Example 29 (First Step of Method a)

Following the procedure of Example and using an equivalent amount of a suitable ethyl 4- [N-aryl-N- (arylacetyl) amino] -1-piperidinecarboxylate as starting material, the following compounds are prepared: N- (2, 6- dimethylphenyl) -N- (4-piperidyl) -2-thiophenacetamide, m.p. 128 ° C; N- (4-chlorophenyl) -N- (4-piperyl) -2-thiophenacetamide, hydrochloride, m.p. 201.5 ° C; 36

DK 153474B

4-chloro-N- (4-chlorophenyl) -N- (4-piperidinyl) -4-benzene-acetamide, hydrochloride, m.p. 222 ° C and N- (4-chlorophenyl) -4-methyl-N ( 4-piperidyl) benzeneacetamide, mp 121 ° C.

Example 30 (First Step of Method a)

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-piperidine carboxylate, 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 is 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-; piperidyl) benzeneacetamide are obtained, m.p. 129.5 ° C.

Example 31 (First Step of Process a) 20 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- 4- N- (4-chlorophenyl) -N - [(3-methoxyphenyl) acetyl] amino] -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 is 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'-30 oxybisethane and hexane to give 7.8 parts of N- (4-chlorophenyl) -3-methoxy-N- (4-piperidyl) benzeneacetamide, mp 85.7 ° C.

Example 32 (Second Step 1 Method a)

To a stirred slurry of 5 parts of N- (4-chlorophenyl) -N- (4-piperidyl) benzeneacetamide, 5 parts of sodium carbonate, a few 35 crystals of potassium iodide in 200 parts of butanol is added dropwise 4 parts

DK 153474B

37 2-bromopropane at room temperature. After the addition is complete, it is all stirred and kept under reflux for 20 hours. Then a second 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 1,1'-oxybisethane and 2-propanone. The precipitated solid salt is filtered off and crystallized from a mixture of 2-propanol and 2-propanol to form 2 parts of N-10 (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidyl] benzeneacetamide, hydrochloride, mp 263 ° C.

Example 33

Following the procedure of Example 32 and using 15 equivalent amounts of a suitable bromide and a suitable N-aryl-N- (4-piperidyl) arylacetamide, respectively, as the starting material, the following compounds are prepared in hydrochloride salt form;

38 DK 153474 B

---- j, υ υ υ υ υ υ υ υ υ |

no ο ο -ο Ο Ο Ο Ο. ο I

g 'inOmOinOmminInvoU in J

ΠΓΜοσ'νΟ'ΨΓ ^ '-' Ο'-ιοοτ ^ in [

f'-ooot'-vovovonit '^ vnvon} tt * J

cvjMniMnJnjfsjrJtMnlnirJfvSj Ο ί

CM I

§ ®,: O r- ~ i r — I »—I r-i r— (· —1 r ~ -t * —I r — t 't r ~ * · ή υυυυυυυυυυυυ ο; £ KKKWKEEKEEEK w! Id!

clothing

^!

Φ ffi ^ I

. 1 · ^ ϋ W ^ ®o i cm g £ * i-r ·. -. U 1 W "h .2" i X J "U." "" Ί ϊ h "" J "'^" Ίΐ V Ko9 ΊΊ.1? V S' ΊΊ!

O — O im U Μ U U Ο M1 co ^ U O J

I H *

X Z- <I

in

I J K W vo co co J

r; ° n ° υ fi X I

· * U U i vO vO I

^ i i cn ο O i ^ n ^^^ ^ x ** i * * · j * · 'j * i <j <{ij η η ϊ n ffi n K ffi K njffiffi i

vO * r «nD t vO ^ 7 * \ 0 nO vO <CT vO I

0 S ϋϋόϋδϋϋΡϋϋϋ;

Uvi ^ uuo ^ uoo ^ ou;

1 ..III .III .11 J

- -; —— i

'I

CO 'x

υ I

X 'liffiKffiiriKWffiKKi S \ j ουυυυυυουυυ, | H i i i i i i i i - 1 i j N N N N N N N N _nJ _cM ^ _ni ^ _ni ► £ Q i

'Ίο' Ίο 'Ίο CO' Ίο 'Ίο' Ίο CO «Ο CO CO ·> * 1 J

u i ί5 I

____— .........- I

39

DK 153474B

-: -., 0 υ υ o, o o o o q in in uy in S in h * c * - co cvj r- m co

(\ J rH rH H

e

M rH rH -rH rH

o υ υ υ υ ΜΗ hi H-ι hi hi 4J »H HH MH hi

1-I

ω. m in m m n ffi ffi K ffi ^ ό o υ υ ^ 'Φ ^^ w w w w w

vO vD vD O

»J υ υ υ υ

<J I 1 I I

rH rH H rH

υ o υ υ to φ φ φ φ (Μ

S

υ Ν κ ο

CO

Η g ^ κ "1 1 ^ μ m ro υ ^ - κ 'Κ Κ Ο η νΟ · Κ υ υ υ Ο β β β

__! 111 I I II

40 DK 153474 B

Example 34.

ψ

To a stirred and hot (40 ° C) mixture of 5 parts of N- (4-chlorophenyl) -N- (4-piperidyl) benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide and 200 parts of n-butanol 05 is added 3 / 75 parts of bromocyclopentane and it is all stirred and kept under reflux for 21 hours and 30 minutes. Then another portion of 5 parts of bromocyclopentane / is added and stirring is continued at reflux temperature for an additional 30 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The oily residue solidifies by trituration in 1,1 * -oxybisethane. The solid product is filtered off and crystallized from 1 / 1'-oxybisethane to give 1.1 part of N- (4-chlorophenyl) -N- (1-cyclopentyl-4-piperidyl) benzeneacetamide, m.p. 139.5 ° C .

Example 35.

Following the procedure of Example 34 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 at 1 L-1- Ar Ar melting point

(CH3) 2-CH-4-F-CgH4 CgH5 108.5 ° C

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

\

DK 153474B

41 ΓΪ I l.i L Ar Ar m.p.

(CH 3) 2-CH-4-Br-C 6 H 4 C 2 Hg 97 ° C

(CH3) 2-CH-4-C1-C6H4 2-C1-C6H4 143.2 ° C

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

(ch3) 2-ch-4-Cl-C6H4 3-Cl-C6H4 61.6 ° C

(CH3) 2-CH-2-Cl, 6-CH3-C6H3 4-C1-C6H4 94.2 ° C

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

(CH3) 2-CH-2f5- (Cl) 2-C6H3 4-C1-C6H4 102.5eC

(CH3) 2-CH2,6- (Cl) 2-C6H3 4-C1-C6H4 129.1 ° C

(CH3) 2-CH-2-Cl-C6H4 C6H5 87.5eC

Example 36.

. To a stirred and refluxed mixture of 5 parts of N- (4-chlorophenyl) -N- (4-piperidyl) benzeneacetamide, 5 parts of sodium bicarbonate and 200 parts of benzene is added portionwise 6.7 parts (bromomethyl) cyclopropane, and stirring and reflux heating is continued for 23 hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The semi-solid residue

DK 153474B

42 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-piperidyl] benzeneacetamide, hydrochloride, mp 224 ° G.

Example 37.

To a stirred solution of 5 parts of N- (4-chlorophenyl) -N-10 (4-piperidylbenzeneacetamide, 3.8 parts of N, N-diethylethanamine in 200 parts of benzene is added portionwise 5 parts of 3-bromo-1-propene). addition, 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 hydrogencarbonate solution and water one after the other, dried over potassium carbonate and evaporated. -oxybisethane and 2-propanone to give 4 parts of N- (4-chlorophenyl) -N- [1- (2-propenyl) -4'-piperidyl] benzenacetamide, hydrochloride, m.p. 225.5 ° C .

Example 38

Following the procedure of Example 37 and using an equivalent amount of an appropriate N-aryl-N- (4-piperidyl) -arylacetamide in place of the N - (4-chlorophenyl) -N- (4-piperidyl) used therein ) benzeneacetamide, the following compounds are prepared: N- (2,6-dimethylphenyl) -N- [1- (2-propenyl) -4-piperidin-2-25 thiophenacetamide, hydrochloride, m.p. 203.5 ° C and N - (2,6-Dimethylphenyl) -N- [1- (2-propyl) -4-piperidyl] -benzeneacetamide, hydrochloride, m.p. 214 ° C.

Example 39

For a hot slurry of 5 parts of N- (4-chlorophenyl) -N-

DK 153474B

43 f * (4-piperidyl) benzeneacetamide, 5 parts sodium carbonate, a few * crystals of potassium iodide in 200 parts n-butanol are added 4 parts 2-chloro-2-methylpropane at a temperature of 30 - 40 ° C. It is all stirred and kept under reflux for 140 hours 05, during which 35 parts of 2-chloro-2-methylpropane are added 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-10 solid residue is dissolved in a mixture of methylbenzene, dimethoxyethane and 1,1'-oxybisethane. The solution is filtered from some impurities and the filtrate is evaporated again. From the oily residue, the hydrochloride salt of 1, 1-oxybisethane is prepared in the usual manner to form, after recrystallization of the crude solid salt from 2-propanone, from 0.9 parts of N- (4-chlorophenyl) -N- [1- ( 1,1-dimethylethyl-4-piperidyl] benzeneacetamide, hydrochloride, mp 221 ° C.

Example 40.

A mixture of 4 parts of iodoethane, 5 parts of N- (2,6-dimethyl-phenyl) -N- (4-piperidyl) benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of benzene is stirred and kept heated at reflux for 23 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-piperidyl) benzene acetamide, m.p. 86.5 ° C.

Example 41.

Following the procedure of Example 40 and using an equivalent amount of an appropriate N-aryl-N- (4-piperidyl) -30 arylacetamide in place of the N- (2,6-dimethylphenyl) -N- (4-piperidyl) benzeneacetamide, the following compounds are prepared:

DK 153474 B

44 2-chloro-N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) -benzeneacetamide, hydrochloride, mp 234.6 ° C; N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) -3-methylbenzeneacetamide, m.p. 78.5 ° C; 05 N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) -4-methylbenzeneacetamide, m.p. 50 ° C and N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) ) -4-fluoro-benzeneacetamide, mp 62.3 ° C.

Example 42

To a stirred and refluxed mixture of 5 parts of 4-chloro-N- (4-chlorophenyl) -N- (4-piperidyl) benzene acetamide, 5 parts sodium carbonate, 0.4 parts potassium iodide and 200 parts butanol 7 parts of 1-iodopropane and it is all stirred and refluxed for 22 hours. Then another portion of 4.5 parts of 1-iodopropane is added and stirring and heating under 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-piper: dyl) benzeneacetamide, 20 118 ° C.

Example 43

To a stirred solution of 4 parts of N- (4-chlorophenyl) -N- (4-piperidyl) benzeneacetamide and 3 parts of Ν, Ν-diethylethanamine in 25 200 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 from

DK 153474 B

45 is filtered and dried to give 3.5 parts of N- (4-chlorophenyl) -N- (1-propyl-4-piperidyl) benzeneacetamide, hydrochloride, mp 233.5 ° C.

Example 44

Following the procedure of Example 43 and using 05 an equivalent amount of a suitable iodine alkane and a suitable N-aryl-N- (4-piperidyl) arylacetamide, respectively, in place of the 1-iodopropane and N- (4-chlorophenyl) used therein, respectively. -N- (4-piperidyl) -benzeneacetamide, the following compounds are obtained: N- (2,6-dimethylphenyl) -N- (1-ethyl-4-piperidyl) -2-thi-acetamide, hydrochloride, m.p. 258 ° C; N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) -2-thiophenethylamide, hydrochloride, mp 220.5 ° C; N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) benzeneacetamide, hydrochloride, m.p. 215 ° C; 4-chloro-N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) benzeneacetamide, hydrochloride; mp 224 ° C and N- (4-chlorophenyl) -N- (1-propyl-4-piperidyl) -2-thiophene-2q acetamide, mp 241 ° C.

Example 45

A mixture of 4.5 parts of N- (1-cyclopentyl-4-piperidyl) -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-methylbenzene acetyl 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.

46 DK 153474B

The residue is converted to the ethanedioate salt in 2-propanol. The salt is filtered and crystallized twice, first from ethanol and then from methanol to give 1 part N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (2-pyrimidyl) benzeneacetamide, ethanedioate, m.p. + 1 ° C.

Example 46.

Following the procedure of Example 45 and using equivalent amounts of a suitable N-aryl-4-piperidinamine 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: Ϊ 1 '- f NC-CH - Ar I 2

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

V 3-Pyridyl C 6 H 5 (E) -2-Butenedioate 219.6 ° C

Γν 3-pyridyl 3-CH-C ^H (E) -2-butenedioate 250.3 ° C

/ · J b 4

2-pyridyl. 3-Cl-C C (COOH) 2 205.9 ° C

2-pyridyl. 3-CH3-C6H4 base 107.8 ° C

9 47

DK 153474 B

Π. Ϊ base or L ____ ^ __ salt form smP *

2 - 2-Pyridyl 4-C1-C12. base 119, 2 ° C

| 2-pyridyl 2-thienyl base 129.4 ° C

D-2-pyridyl C (> H5 base 108.8 ° C

2-pyrimyl dyl. C 6 H 5 (COOH) 223.5 ° C

(CH3) 2-CH-3-pyridyl base 129.4 ° C

(CH3) 2-CH-3-pyridyl 3-C1-C6H4 base 117.7 ° C

(CH 3) 2-CH-3-pyridyl 4-C 1 -C 4 base 146, 6 ° C

(CH3) 2-CH-3-pyridyl. 2-thienyl base 126.7 ° C

(CH 3) 2-CH-3-pyridyl 3-CH 2 C 2 H 3 base 100 ° C

(CH3) 2-CH-2-pyridyl 3-C1-C6H4 base 102.6 ° C

(CH3) 2-CH-2-pyridyl base 72, leC

(CH 3) 2-CH-2-pyr. dyl 4-Cl-C 2 K 3 base 83.3 ° C

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

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

(CH3) 2-CH-2-pyrimidyl; 4-Cl-C2 (COOH) 2 195.7 ° C

Example 47.

A mixture of 5 parts of methyl 1- (1-methylethyl) -4- (phenylamino) -4-piperidinecarboxylate, 24 parts of 4-chlorobenzene acetyl chloride, 4 parts of sodium carbonate and 180 parts of dimethylbenzene is stirred and heated under reflux for 32 hours. The reaction mixture is cooled, washed with a dilute sodium hydroxide solution and extracted with a dilute hydrochloric acid solution: 3 layers are obtained.

I- 48

DK 153474B

The oil and aqueous phase are combined and made alkaline with a dilute sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is converted to the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane to give 5 parts (48%) of methyl-4- [N- (4-chlorophenyl) acetyl-N-phenylamino] -1- (1 (methylethyl) -4-piperidinecarboxylate, ethanedioate, mp 154.2 ° C.

Example 48.

Following the procedure of Example 47 and using equivalent amounts of a suitable 4-aryl-amino-4-piperidine carboxylate and a suitable aryl-acetyl chloride, respectively, as starting materials, the following compounds are obtained in free base form or after treatment with the appropriate acid in acid addition salt form:

II

r \ C-O-R

IA-NV 1 \ _ / T-S-CH 2-Ar 0 ri, 1 r, base or L Ar R salt form Mp *

(CH3) 2-CH-3-CH3-CgH4 C2H5 (COOH) 2 198.4 ° C

(CH3) 2-CH-C6H5 C2H5 (E) -2-bi-168.5 ° C

dioate

DK 153474B

49 ψ τ 1 λ 1 base or L Ar__R salt form___ (CH3) 2-CH-2-thienyl (COOH) 2 156 * 8 * 0 (CH3) 2-CH-4-Cl-C6H4 C2H5 HCl.191.5 * 0

(CH3) 2-CH-3-CH3-C6H4 CH3 (COOH) 2 170 ° C

(CH3) 2-CH-3-Cl-C6H5 CH3 (COOH) 2 152.2 ° C

(CH 3) 2-CH-C 6 H 5 CH 3 (COOH) 2 165.5 ° C

(CH3) 2-CH-2-thienyl CH3 (COOH) 2 173., 6 ° C

P) · 4-Cl-C 2 H 4 (E) 2-Butenedioate 195.6 ° C

py G6H5 C2H5 (E) _2 butenedioate 203.3 ° C

py 3-Cl-C 2 H 4 G 2 5 (E) -2-btttendioate 207.8 C

3-CH3-C6H4 C2H5 (E) .2Butendioate '88, 1'C

Q. C6H5 CH3 (COOH) 2 197.2 ° C

ΓΥ 2-thienyl CH 3 (COOH) 2 166.4 ° C

ΓΥ 3-Cl-C & H4 CHj. base 94 ° C

ΓΥ 3-CH3-C6H4 CH3 (COOH) 2 189.5 "C

Example 49.

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

DK 153474B

50 e · in 2,21-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 50. '

Following the procedure of Example 49 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 10 with the appropriate acid in acid addition salt form: I 2

Ar T1 *, 1 base or L Ar Ar salt form. SMP '

(CH3) 2-CH-CgH5 3-CH3-C6H4 HCl 173.6 ° C

(CH3) 2-CH-CgH5 3-Cl-C6H4 HCl 204.8 ° C

(CH3) 2 ~ CH-CgH5 2-thienyl (E) -2- [t] - 168.1 ° C

CH3 2.6- (CH3) 2-C6H3 CgH5 base 95.5 ° C

CH3 4-Cl-C6H4 CgH5 base 115 ° C

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

nC3H? 2,6- (CH3) 2-CgH3 2-thienyl (COOH) 2 153 ° C

DK 153474B

51 - 1 "ΓΊ base or L__Ar__Ar salt form__Smp · <

nC3H? 2.6- (CH3) 2-C6H3 C6H5 (COOH) 2 16l ° C

CH2 = CH-CH2 4-Cl-C6H4 2-thienyl. HCl 227-, 5eC

C6H5 2-thienyl base 119 ° C

Q-3-pyridinyl 4-Cl-C 2 H 3 base 149.9 ° 0

3-pyridinyl 3-Cl-C 2 HCl, 1 / 2H 2 O 236.6 ° C

Q-3-pyridinyl 2-thienyl base 15998 ° C

„» _ ™ .I —.........., I '"· 1" "" P "^" *, --- Ί

Example 51.

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 05 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

DK 153474B

After refluxing for an additional 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 05 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 52

Following the procedure of Example 51 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: bromo-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, mp 104.9 ° C.

Example 53.

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

DK 153474B

53 is dried to give 7.5 parts of 4-chloro-N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidyl] benzeneacetamide, hydrochloride, mp 266.6 ° C.

Example 54

05 From 6 parts of N- [1- (1-methylethyl) -4-piperidyl] -N-phenyl-2-thiophenacetamide, (E) -2-butenedioate is released in the free base 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 salt 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 55

From an aqueous solution of 2.8 parts of N- (2,6-dimethylphenyl) - N- (1-propyl-4-piperidyl) -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 20 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-piperidyl) -2-thiophenacetamide, mp 62.5 ° C.

Example 56.

From 3.9 parts of N- (1-cyclopentyl-4-piperidyl) "3-methyl.-N- (3-pyridinyl) 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 salt in ethanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane to form 3 parts of N- (1-cyclopenty1-4-piperidinyl) -3-methyl-N- (3-pyridinyl) -benzeneacetamide, ethanedioate, mp 192.6 ° C.

Example 57.

A mixture of 50 parts of 4- (phenylamino) -X- (phenylmethyl) -

54 DK 153474 B

4-piperidinecarboxamide and 600 parts of concentrated hydrochloric acid solution are kept under reflux 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, 05 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) -10 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 off 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 heated 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 25 172 parts of sodium dihydro-bis (2). -methoxyethoxy) aluminate, 70% in benzene, in 160 parts 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 35 is released in a conventional manner. After extraction with 1,1'-oxybisethane, the base is washed with water, dried and evaporated to give

DK 153474B

55 of 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-piperidinemethanol in 90 parts of benzene is added 0.2 parts of Q5 Ν, Ν, Ν-triethylbenzene methanedium 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.

After the addition is complete, stirring is continued at room temperature, first for 2 hours and 30 minutes, and after the addition of another 10 portions 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.

2q 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.

DK 153474B

56

A mixture of 10 parts of 2-bromopropane, 9 parts of 4- (methoxy-methyl) -N-phenyl-4-piperidinamine, 4.9 parts of N, N-diethylethane-amine and 72 parts of Ν, Ν-dimethylacetamide is stirred and maintained. heated at 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.

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 benzene acetyl chloride in 45 parts of benzene. 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 20 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.

DK 153474B

57

Example 58 -

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 9 parts [4- (2-chloro-phenyl)]. 2-oxoethyl) phenyl] ethyl carbonate. After the addition is complete, the whole is heated under 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 combined and the eluent is evaporated to give 5.5 parts of 4- [2- (4-chlorophenyl) - [1- (1-methylethyl) -4-piperidyl] amino] -2-oxoethyl] phenyl] ethyl carbonate as an oily residue.

A mixture of 5.5 parts of 4- [2- (4-chlorophenyl) [1- (1- methylethyl) -4-. giperidyl] amino [2-oxoethyl] phenyl] ethyl carbonate and 50 parts of sodium hydroxide solution 10% are 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 the 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-piperidyl] benzeneacetamide, mono -30 hydrochloride, mp 242.9 ° C.

Claims (3)

1. Analogous process for the preparation of N-aryl-N- (4-piperidyl) arylacetamido derivatives of the general formula 10 x L1 - / - Y (1H) - / XN-C-CH2-Ar Ar 15 or pharmaceutically acceptable acid addition salts thereof, wherein: L 1 represents (C 1 -C 3) alkyl, (C 3 -C 8) cycloalkyl, (C 1 -C 8 cycloalkyl-C 1 -C 6) 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 1 represents phenyl, mono- or di-substituted phenyl 25 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 8) alkyloxy, and X represents hydrogen, (C 1 -Cg) alkyloxycarbonyl or (C1-Cg) alkyloxymethyl, provided that is different from (Cg-Cg) cycloalkyl when Ar and Ar1 are both phenyl or substituted phenyl and X is hydrogen, KNOWN Suitable for a) subjecting a compound of the general formula (B) to C (CH) - Ar (2) Ar is wherein Ar and Ar1 have the meaning given above and X1 represents hydrogen or (C1-C6alkyloxymethyl, and Z represents (C1-C8) -10 alkoxycarbonyl, an elimination reaction, the compound (IV) subjected to acidic or basic hydrolysis to Preparation of a Compound of Formula / - \ / X1 (Ia) H \ X 1 \ - '' NC-CH_-Ar I 2 Ar wherein Ar, Ar1 and X1 have the above meanings, which compound (Ia) is then N-alkylated to produce a compound of formula,, *. . (I> Ar wherein Ar, Ar1, L · 1 and X1 have the meanings set forth above, by reaction with a compound of formula L ^ -Y wherein L · 1 30 has the above and Y is a suitably reactive group, preferably a halogen atom, in a reaction-inert organic solvent, preferably in the presence of a base, or b) acylating a compound of formula 35, ηνη (VII) Ar 05 is an arylacetyl halide of formula O halogen-1z-CH 2 -Ar1 (III) wherein Ar, Ar1, L1 and X have the above meanings, in a suitable reaction-inert organic solvent, preferably in the presence of a base, when Ar 1 in the final compound (I) is mono- or di-hydroxyphenyl, introduces a protective group into the starting compound (III) and after preparation of the final product, these protective groups are removed by alkaline hydrolysis, after which a compound prepared by a) or b), if desired, is converted into a pharmaceutical acceptab or acid addition salt thereof. A process according to claim 1 for the preparation of N- (4-chlorophenyl) -N [1- (1-methylethyl) -4-piperidyl] benzeneacetamide or pharmaceutically acceptable acid addition salts thereof, characterized by reacting N- (4-chlorophenyl) ) -N- (4-piperidyl) -benzeneacetamide with 2-bromopropane and, if desired, converts the compound prepared to a pharmaceutically acceptable acid addition salt thereof. Process according to claim 1 for the preparation of N- (4-chlorophenyl) -N- (1-ethyl-4-piperidyl) benzeneacetamide or pharmaceutically acceptable acid addition salts thereof, characterized in that N- (4-chlorophenyl) is reacted with - N- (4-piperidyl) benzeneacetamide with ethyl iodide and, if desired, converts the compound prepared to a pharmaceutically acceptable acid addition salt thereof. 35