KR860000590B1 - Process for preparing 4-(5-chloro-2-oxobenzimidazolin-1-yl)-1-(3-(2-oxobenzimidazolin-1-yl)propyl)-piperidine and salts thereof - Google Patents

Abstract

4-(5-Chloro-2-oxobenzimidazolin-1-yl)-1-[3-(2-oxobenz imidazolin-1- yl) propyl -piperidine(I) and its salt used as an analgesic was prepd. from 4-(5-chloro-2-oxobenzimidazolin-1-yl)-1[2-hydroxy-3-(2- oxobenzimidazolin-1-yl) propyl!-piperidine(VI) by contact redn. in dehydrated toluene. (VI) was prepd. from 4-( 5chloro-2- oxobenzimidazolin-1-yl)-1-(2-hydroxy-3-chloropropyl)piperidine(IV) by reacting with 2-oxobenzimidazoline(V). (IV) was prepd. from 4-(5- chloro-2-oxobenzimidazolin-1-yl) piperidine(II) by reacting with epichlorohydrine(III) in 85 % formic acid.

Description

4- (5-Chloro-2-oxobenzimidazolin-1-yl) -1- [3- (2-oxobenzimidazolin-1-yl) propyl] -piperidine and its salt

The present invention is 4- (5-chloro-2-oxobenzimidazolin-1-yl) -1- [3- (2-oxobenzimidazolin-1-yl) represented by the following general formula (I). Propyl] -piperidine and salts thereof.

The compound of formula (I) is a known substance and is known as a drug having an anti-earth action.

Many known production methods containing the known compounds are known, for example.

1. In Korean Patent No. 10053, a method of preparing the following compound of formula (I) by reacting a compound of formula (II) in a compound of formula (III) with an organic solvent:

In the above formula, R ¹ , R ² , R ³ , A and B ¹ are the same as in the specification of Patent No. 10053.

2. Korean Patent No. 11162 discloses an intermediate of Structural Formula (6) by condensing a compound of Structural Formula (4) obtained by condensing a compound of Structural Formula (II) with a compound of Structural Formula (3) in the presence of sodium amide. A method for preparing a benzimidazolinone derivative of formula (1) by preparing and reducing the compound of formula (6) by known methods is described.

The present invention relates to a method for producing the target compound in a high yield in a different process from the known method.

The method of the present invention is described in detail as follows.

When 4- (5-chloro-2-oxobenzimidazolin-1-yl) piperidine of the following formula (II) is reacted with epichlorohydrin of the following formula (III) in about 85% formic acid at room temperature -[4- (N-2-hydroxy-3- (1-benzoimidazoline-2-keto) propyl) piperidyl] -5-chloro-2-benzoimidazoline is obtained in good yield, This compound is reacted with 2-oxobenzimidazolin of formula (V) in the presence of an acid acceptor to yield 4- (5-chloro-2-oxozenzimidazolin-1-yl) -1- of formula (VI). [2-hydroxy-3- (2-oxobenzimidazolin-1-yl) propyl] -piperidine is obtained in good yield.

Next, 4- (5-chloro-2-oxobenzimidazol-1-yl) -1 of structural formula (VII) obtained by dehydrating the compound of formula (VI) in toluene in the presence of a p-toluenesulfonic acid dehydrating agent. -[3- (2-oxobenzimidazolin-1-yl) prop-2-en-2-yl] piperidine by catalytic reduction and conversion to its pharmaceutically usable acid addition salt if necessary Compound (I) is prepared and represented by the following scheme.

Reaction of 4- (5-chloro-2-oxobenzimidazolin-1-yl) piperidine of formula (II) with epichlorohydrin of formula (III) is ethanol, n-propanol, n- It is preferable to carry out at reflux temperature in a solvent such as alcohol such as butanol or n-pentanol.

The reaction is completed in 2-12 hours. The compound of structural formula (IV) thus obtained, namely 4- (5-chloro-2-oxobenzimidazolin-1-yl) -1- (3-chloro-2-hydroxypropyl) -pyriridine, is conventional It is dissolved in an organic solvent such as methylene chloride, ethanol, toluene and the like and reacted with 2-oxobenzimidazolin of formula (V) without separation or further purification by a method such as evaporation under reduced pressure.

This reaction is carried out in the presence of an organic or inorganic base amine (preferably tertiary amine). The compound of formula (VI) thus obtained, namely 4- (5-chloro-2-oxobenzimidazolin-1-yl) -1- [2-hydroxy-3- (2-oxobenzimidazolin-1 -Yl) propyl [piperidine is dehydrated in the presence of sulfuric acid or sulfonic acid to yield 4- (5-chloro-2-oxobenzimidazolin-1-yl) -1- [3- (2 Oxobenzimidazolin-1-yl) prop-2-en-2-yl] piperidine and 4- [5-chloro-2-oxobenzimidazolin-1-ene of structural formula (VII ') 1-yl] piperidine was obtained.

The compounds of formulas (VII) and (VII ') thus obtained are separated by a known method such as neutralizing the mixture with an alkali metal hydroxide or carbonate, extracting with an organic solvent, dehydrating and evaporating the solvent.

The mixture of structural formulas (VII) and (VII ') thus obtained was then catalytically reduced using palladium / charcoal as a catalyst to give 4- (5-chloro-2-oxobenzimidazolin-1-yl of formula (I). ) -1- [3- (2-oxobenzimidazolin-1-yl) propyl] piperidine. The compound of formula (I) thus obtained is crystallized and purified, and if necessary, can be converted into acid addition salt, which is pharmaceutically usable by conventional methods.

EXAMPLE

(a) Preparation of 1- [4- (N-2-hydroxy-3-chloropropyl) piperidine] -5-chloro-2-benzimidazolone.

100 g of epichlorohydrin is added to a solution of 220 g of 4- (5-chloro-2-oxobenzimidazolin-1-yl) piperidine dissolved in 1 liter of 85% formic acid. After the addition is complete, stir at room temperature for 4 hours.

Ice was then added to the residue, which was vacuum distilled at 50 DEG C, neutralized by addition of concentrated ammonia water and then extracted with chloroform. The extract is dehydrated with magnesium sulfate and dried under reduced pressure to obtain the title compound. This compound is used in the next step.

(b) 4- (5-chloro-2-oxobenzimidazolin-1-yl) -1- [2-hydroxy-3- (2-oxobenzimidazolin-1-yl) propyl] pyrreri Preparation of Dean.

A mixture of 70 g of 2-benzimidazolone 134 kg k ₂ CO ₃ and 1 l of dimethylformamide was stirred at 80 ° C. for 3 hours, cooled to room temperature, poured into water, and then the resulting compound was precipitated. Filtration and drying gave the title compound, which was used as is in the next step.

(c) Preparation of 4- (5-chloro-2-oxobenzimidazolin-1-yl) -1- [3- (2-oxobenzimidazolin-1-yl) propyl] piperidine.

A mixture of 100 g of the compound obtained in step (b), 899 ml of toluene and 15 g of p-toluenesulfonic acid was refluxed.

The water produced during the reaction is continuously separated off by water trap. After completion of the reaction, the obtained reaction intermediate was cooled, filtered, washed with water and dried to dissolve the residual intermediate in acetic acid, and 5% Pd / c was added in a catalytic amount, and then hydrogenated at 40 ° C under atmospheric pressure. After the reaction is complete, it is cooled, poured into ice water and neutralized to neutral. The precipitate obtained is filtered to give 82 g of the title compound.

Claims (1)

Obtained by reacting 4- (5-chloro-2-oxobenzimidazolin-1-yl) piperidine of formula (II) with epichlorohydrin of formula (III) in about 85% formic acid 4- (5-Chloro-2-oxobenzimidazolin-1-yl) -1- (2-hydroxy-3-chloropropyl) -piperidine of formula (IV) in the presence of an acid acceptor Reaction with 2-oxobenzimidazolin of (V), 4- (5-chloro-2-oxobenzimidazolin-1-yl) -1- [2-hydroxy- of the following structural formula (VI) obtained The 3- (2-oxobenzimidazolin-1-yl) propyl] piperidine was subjected to catalytic reduction of an intermediate in dehydrated toluene in the presence of a dehydrating agent to give 4- (5-chloro-2-oxo of formula (I) A process for preparing benzimidazolin-1-yl) -1- [3- (2-oxobenzimidazolin-1-yl) propyl] piperidine.