DD255161A5 - PROCESS FOR PREPARING 1 - ((4-FLUORPHENYL) METHYL) -N- (1- (2- (4-METHOXYPHENYL) ETHYL) -4-4PIPERIDINYL) -1H-BENZIMIDAZOLE-2-AMINE - Google Patents

Abstract

Process for the preparation of 1- & (4-fluorophenyl) methyl! N-1- & 2- (4-methoxyphenyl) ethyl! -4-piperidinyl-1H-benzimidazol-2-amine, consisting of the reaction of 4-amino-N - & 2- (4-methoxyphenyl) ethyl! Piperidine with 2-chloro-1- & (4-fluorophenyl) methyl! -1H-benzimidazole, in an inert solvent medium and isolation of the required product by conventional methods is disclosed.

Description

characterized in that 4-amino-N- [2- (4-methoxyphenyl) ethyl] piperidine of the formula

H ₀ N - (N - CH ₉ CH ₉ - / n - OCH ^ \ I * *

with 2-chloro-1 - [(4-fluorophenyl) methyl] -1H-benzimidazole of the formula III

Cl

is reacted in an inert solvent medium.

2. The method according to claim!, Characterized in that the compounds of the formula II and III are used in a molar ratio of 1: 1 of the stoichiometric reaction.

3. Process according to claims 1 and 2, characterized in that it is carried out in an organic solvent.

4. The method according to claim 3, characterized in that the organic solvent is selected from isoamyl alcohol, N-methylpyrrolidone, cresol, phenyl, diethylene glycol dimethyl ether.

5. The method according to any one of the preceding claims, characterized in that the reaction at a between 150 ⁰ C and 230 ⁰ C, preferably between 19O ⁰ C and 210 ° C, temperature is carried out.

6. The method according to any one of the preceding claims, characterized in that it is carried out under pressure.

7. The method according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of a collecting agent for the liberated hydrochloric acid.

8. The method according to any one of the preceding claims, characterized in that it is the collecting agent is sodium or potassium carbonate, triethylamine, pyridine or the compound of formula II.

Field of application of the invention

The invention relates to a process for preparing 1 - [(4-fluorophenyl) methyl] - N - {1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl} -1H-benzimidazol-2-amine, a synthetic product of therapeutic interest. This product has the following formula I

OCH.

Characteristic of the known state of the art

For the preparation of the above compound (title compound), various methods are already known. In EP-PS 5.318 several methods are described in which the formation of the benzimidazole ring by means of an N, N'-disubstituted thiourea, which in turn is prepared from an isothiocyanate.

In another method (J.B. A. Thijssen et al .. Journal of Labeled Compounds and Radio Pharmacaceuticals, Vol. XX [7], 861,

1983), the title compound is prepared from 2-chloro-1 - [(4-fluorophenyl) methyl)] - 1H-benzimidazole and 4-amino-N- [2- (4-methoxyphenyl) ethyl] piperidine. The latter compound is very expensive, due to the time-consuming manufacturing process, in the absence of a solvent, heated to 13O ⁰ C for 41 hours.

Finally, preparation of the title compound in chemically pure form requires chromatographic purification in a silica gel column.

Both the high consumption of 4-amino-N- [2- (4-methoxyphenyl) ethyl] piperidine and the requirement of chromatographic purification make the manufacturing process extremely expensive.

Object of the invention

With the invention, the indicated deficiency of the prior art should be eliminated.

Explanation of the essence of the invention

The process for producing the above-mentioned product is by reacting 4-amino-N- [2- (4-methoxyphenyl) ethyl] piperidine represented by the following formula II

H ₂ N - / ~~ \ n ^-CH ₂ CH ₂ - \ ^OVOCH 3 · (ID

with 2-chloro-1 - [(4-fluorophenyl) methyl] -1H-benzimidazole of the following formula III

(III)

characterized in an inert solvent. The required product is isolated by conventional means.

The reactants are preferably used in a molar ratio of 1: 1 of the stoichiometric reaction.

The reaction may be carried out in an organic solvent such as isoamyl alcohol, N-methylpyrrolidone, cresol, phenol, diethylene glycol dimethyl ether, etc.

The method can 190 ° Cund210 ° C temperatures, which are run under Rückflußdruck of the solvent used at between 150 ⁰ C and 230X, preferably.

The process can be carried out in the presence of a scavenger for the liberated hydrochloric acid, it being recommended. Use sodium or potassium carbonate, triethylamine, pyridine or the same reactive amine of formula II. If desired, the process may be carried out in the presence of a catalyst such as electrolytic copper or a salt thereof, namely copper chloride, sulfate or oxide.

Upon completion of the addition, the required product is isolated by conventional methods and recrystallized from an organic solvent such as ethanol, isopropanol, ethyl acetate, etc. to give chemically pure 1 - [(4-fluorophenyl) methyl] -N- {1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl} -1H-benzimidazol-2-amine to win.

Next, a number of non-limiting examples will be described.

embodiments example 1

A mixture of 30.7 g (0.1 mol) of 4-amino-N- [2- (4-methoxyphenyl) ethyl] piperidine dihydrochloride, 26.05 g (0.1 mol) of 2-chloro-1 - [(4-fluorophenyl ) methyl] -1 H-benzimidazole and 20,9g (0,15MoI) of potassium carbonate in 150 ml of isoamyl alcohol was heated for 17 hours under stirring in a pressure reactor at 195 ⁰ C. The crude reaction product was poured over water. The organic phase was decanted and the solvent driven off under vacuum. The recovered solid was recrystallized from a mixture of isopropanol / water (1: 1). 36.6 g (yield 80%) of 1 - [(4-fluorophenyl) methyl] - N - {1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl} -1H-benzimidazol-2-amine, mp 172 to 173 ⁰ C, were won. IR (KBr):. 3200.3000, 2900, 2750,1600,1560,1500,1460,1340,1280,1220,1080,1020,815,730cm ^"1 The analysis results in the formula: C28H31FN ₄ O, (Relative molecular mass 458 , 25)

 % Calculated: C: 73.32; H: 6.82; N: 12.22; F: 4,15; % Found: C: 73.41; H: 6.79; N: 12.31; Q: 4,10.

Example 2:

A mixture of 4.64 g (0.02 mol) of 1-amino-N- [2- (4-methoxyphenyl) ethyl] piperidine base, 5.21 g (0.02 mol) of 2-chloro-1 - [(4-fluorophenyl ) Methyl] -1 H-benzimidazole and 1.4 g (0.01 mol) of potassium carbonate in 30 ml of N-methylpyrrolidone was refluxed for 18 hours with stirring. The solvent was expelled under vacuum and 100 ml of CHCl ₃ and 100 ml of an aqueous solution of potassium carbonate (10%). The organic phase was decanted, dried and concentrated to dryness. The residue was crystallized from 2,2'-oxy-bis-propane to give 5.95 g (yield 65%) of 1 - [(4-fluorophenyl) methyl] -N- {1- [2- (4-methoxyphenyl) ethyl] ] -4-piperidinyl} -1H-benzimidazol-2-amine having the same characteristics as the product obtained in Example 1.

Example 3:

A mixture of 7.02 g (0.03 mol) of 4-amino-N- [2- (4-methoxyphenyl) ethyl] piperidine base, 7.81 g (0.03 mol) of 2-chloro-1 - [(4- fluorophenyl) methyl] -1H-benzimidazole, 2.1 g (0.015 mol) of potassium carbonate and 0.5 g (0.008 mol) of electrolytic copper in 50 ml of N-methylpyrrolidone was refluxed for 8 hours with stirring. The organic phase was decanted and washed with a solution of dilute HCl and then with water. The organic phase was stripped and concentrated to dryness under vacuum. The residue was recrystallized from ethyl acetate to give 9.6 g (yield 70%) of 1 - [(4-fluorophenyl) methyl] - N - {1- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl} -1H benzimidazole-2-amine having the same characteristics as the product obtained in Example 1.

Claims (1)

Claim: 1. A process for the preparation of 1 - [(4-fluorophenyl) methyl] - N - {- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl} -1H-benzimidazol-2-amine of the formula I, CH. -WH - </ ^N - ^CH 2 ^CH 2 OCH.