KR890003811B1 - Process for preparing n-(2-pyrimidyl) piperazinyl derivatives - Google Patents

Abstract

A process for preparing N-(2-pyrimidyl) piperazilyl alkyl azaspyro alkanedione of formula (I) and its salt comprises (a) reacting a cpd. of formula (II) with a cpd. of formula (II) in the presence of triethyl amine or diethyl amine to produce a cpd. of formula (IV), and (b) reacting the cpd. (IV) with a cpd. of formula (V). In the formulas, M is an alhali metal such as Na or K; R is a lower alkyl. (I) and its salt are used as a neuroleptic.

Description

Method for preparing N- (2-pyrimidyl) piperazinyl derivative

The present invention relates to a novel process for the preparation of the compound N- (2-pyrimidyl) piperazinyl alkylazaspiro alkanedione and salts of the following general formula (I), known as non- habitual neurostabilizers.

The compound represented by formula (I) is a known compound, as in US Pat. No. 3,717,634. First, 8-oxaspiro [4.5] decane-7,9-dione and 1- (4-aminobutyl) -4- (2 -Pyrimidyl) piperazine in a pyridine solvent for a long time reflux, second, 8- (4-halo-1-butyl) -8-azaspiro [4.5] decane-7,9-dione and N- (2-pyrid Although a method of reacting midi) piperazine for a long time has been introduced, the first reaction has the disadvantage of easily generating halfamide in the reaction, but requires a high temperature or a considerable time for the reaction to be completed. In the preparation of 8- (4-halo-1-butyl) -8-azaspiro [4.5] decane-7,9-dione, there is a possibility of formation of a polymer by side reaction, and thus it is not economical method because of low yield and difficult purification. However, the present invention is gentle in the method of preparing the compound of the general formula (I) by reacting with the compound of the general formula (V) using the following compound of the general formula (IV), which is different from the conventional production method. The reaction is completed in a short time under the conditions to provide a new synthesis method to obtain a high-purity target in high yield. The present invention reacts 8-azaspiro [4.5] decane-7,9-dione of the general formula (II) or its inorganic salt with alkylchloroformate of the general formula (III) to give a new compound of general formula (IV). 8-Carboalkoxy-8-azaspiro [4.5] decane-7,9-dione is readily prepared in high yield and is a compound of formula (V) 1- (4-aminobutyl) -4 (2-pyrimidyl) It is a method for preparing the compound of general formula (I) in high yield in a short time by reacting with piperazine at low temperature.

The manufacturing process of the present invention is as follows.

(Wherein M represents an alkali metal such as H, or Na, K, and R represents a lower alkyl group or benzyl group such as methyl or ethyl)

When the present invention is described in more detail, the general formula (II) compound can be easily prepared by reacting with sodium hydroxide, potassium hydroxide, sodium methoxide according to a general method, and as a solvent, alcohols, Halogen alkanes such as acetone, methylene or ethylene chloride are possible.

In order to prepare the compound of formula (IV), which is a novel substance of the present invention, the reaction molar ratio of the compound of formula (II) to the compound of formula (III) is preferably 1: 1.0-1.5 equivalents. As a solvent, benzene, toluene, key Aromatic hydrocarbons such as styrene, halogen alkanes such as methylene ethylene chloride, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dioxa, tetrahydrofuran and the like and a mixed solvent thereof are possible Do. Depending on the solvent, the reaction is almost completed within 1 hour to 3 hours in the range of -5 ° C to reflux temperature. At this time, if a base such as triethylamine, dimethylamine or the like is used in a catalytic amount to 1.0 equivalent, the reaction proceeds rapidly. The preparation of Structural Formula (I), which is an object of the present invention, is carried out using the compounds of Formula (IV) and Structural Formula (V) with water, alcohols, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, Using as a solvent such as N-dimethylacetamide, dimethyl sulfoxide and the like, the reaction is almost completed within 10 hours at room temperature to 100 ° C., and the purified compound can be separated and purified in high yield and purity. At this time, the reaction proceeds rapidly using a catalyst amount of 1.0 equivalent to about 1.0 equivalents of sodium carbonate, potassium carbonate, triethylamine, dimethylamine, and the like, and it is more preferable to use N, N-dimethylformamide, acetamide, dimethyl sulfoxide, etc. as a solvent. desirable. The following examples are intended to enable the present invention to be clearly understood and practiced, but not to limit the present invention. NMR spectra were recorded using an 80 MHz (Bruker) spectrometer and chemical shifts (Shift) were expressed in delta (ppm).

Example 1

8-azaspiro [4.5] decane-7,9-dione sodium salt

After dissolving 8.35 g of 8-azaspiro [4.5] decane-7,9-dione in 50 ml of methylene chloride, 9.6 ml of sodium methoxide solution (28%) was added dropwise. After stirring for 1 hour at room temperature, the mixture was cooled to 0-10 DEG C to obtain 9.1 g (96% yield) of the title compound.

Example 2

8-carboxyethoxy-8-azaspiro [4.5] decane-7,9-dione

9.46 g of Example 1 was suspended in 50 ml of methylene chloride, and 5 ml of ethylchloroformate was added dropwise. Cool to 0-10 ° C. and stir for 10 minutes. The methylene chloride layer is washed with 30 ml of water and dried over anhydrous magnesium sulfate. Filtration and concentration under reduced pressure afforded 11.2 g (yield: 93.7%) of the title compound as an oil.

Elemental Analysis C ₁₂ H ₁₇ NO ₄ (239.27)

Theoretical value (%): C; 60.23%, H; 7.16%, N; 5.85%

Found (%): C; 60.17%, H; 7.17%, N; 5.89%

NMR; 4.2-4.4 (q.2H), 2.6 (s.4H), 1.5-1.8 (m.8H) 1.2-1.45 (t.3H)

Example 3

8- [4- [4- (2-pyrimidyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione

4.785 g of the material obtained in Example 2 and 4.71 g of 1- (4-aminobutyl) -4- (2-pyrimidyl) piperazine are dissolved in 30 ml of dimethylsulfoxide, followed by addition of 2.6 ml of triethylamine. After reaction at 78-80 ° C for 10 hours, the reaction was completed by TLC, and then cooled to room temperature and filtered. 50 ml of water and 30 ml of toluene are added to the filtrate. After stirring for 10 minutes, the water layer was removed and washed twice with 20 ml of water. 5 ml of concentrated aqueous hydrochloric acid solution and 40 ml of water are added to the organic layer, and after stirring for 10 minutes, the water layer is taken, and after alkalinizing with 10% sodium hydroxide solution, it is extracted twice with 30 ml of toluene. After drying over anhydrous magnesium sulfate, 70 ml of water was added thereto, cooled to 0-5 ° C., stirred for 1 hour, and filtered to obtain 6.63 g (yield: 86%) of white-yellow yellow base.

mp 99 ° -120 ℃

TLC (silica gel / hexane: isopropyl alcohol: ammonia = 6: 10: 1)

Rf = 0.6

Example 4

8- [4- [4- (2-pyrimidyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione monohydrochloride

5.78 g of the free base obtained in Example 3 was dissolved in 30 ml of ethanol, 1 equivalent of an isopropyl alcohol saturated hydrogen chloride solution was added dropwise at 50-60 ° C., and gradually cooled to room temperature to precipitate the title compound as crystals. This is filtered and dried to obtain 5.95 g (yield 94%) of monohydrochloride.

Claims (3)

A method of preparing a compound of formula (I) and a salt thereof by reacting a compound of formula (II) with a compound of formula (III) in the presence of a base to obtain a compound of formula (IV).

(Wherein M represents an alkali metal such as Na and K, and R represents a lower alkali group) A process according to claim 1, wherein triethylamine or diethylamine is used as a base when preparing the compound of formula (IV). A process according to claim 1, wherein sodium carbonate, potassium carbonate, triethylamine or diethylamine is used as a base when preparing the compound of general formula (I).