KR890005202B1 - Process for preparing 4,4-dimethyl-1-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidine - Google Patents

Abstract

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Description

Method for preparing 4,4-dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidine dione

The present invention provides the preparation of 4,4-dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidine dione represented by the structural formula (I). It is about a method.

Compounds of the above formula (I) are known compounds and are described in the Journal of Medicinal Chemistry, 26 (2), 194 (1983), US Pat. No. 1,423,049.

U.S. Patent 4,423,049 discloses dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidine dione of formula (I) as follows. It is manufactured by four methods, the same method A, B, C, D.

[Method A]

[Method B]

[Method C]

[Method D]

All of these known manufacturing methods use expensive 2-halopyrimidines to prepare structural formulas (III), (V), (iii) and (iii), which are used as basic starting materials, or through various processes as follows. It is inconvenient to manufacture the material of formula (V).

In particular, the preparation of 1- (4-aminobutyl) -4- (2-pyrimidinyl) piperazine of formula III is 1- (3-cyanopropyl) -4- (2-pyrimidinyl) pipe Razine is a tricky reaction that requires catalyzing raninickel.

Method A was prepared from 3,3-dimethylglutaric anhydride of formula (II) and 1- (4-aminobutyl) -4- (2-pyrimidinyl) pyrazine of formula (III). It is a method of manufacturing, there is an inconvenience to continue to remove H ₂ O while refluxing for 20 hours.

In addition, Method D also reacts 4,4-dimethyl-1- [4- (piperazinyl)] butyl-2,6-piperidine dione with 2-chloropyrimidine of Structural Formula (I) to Structural Formula (I) This method also uses expensive 2-chloropyrimidine to prepare a compound of, there is a drawback to react for a long time at a high temperature of 80 ℃ to 170 ℃.

The present invention provides a method of improving the above-mentioned shortcomings by using 4,4-dimethyl-1- [4- [di (2-haloethyl) amino] butyl] -2,6-piperidine dione of structural formula (XII). Using 2-aminopyrimidine of XIII) as a starting material, it is an economical method that can produce the compound of formula (I), which is the target compound, in a high yield through a relatively simple reaction operation. In addition, since it does not go through intermediates like Structural Formulas (III), (V), (iii), and (iii) as in the previous method, it is very economical that there is no necessity to use expensive 2-halopyrimidine or to prepare it through a multi-step process. And convenient way.

In more detail, the method of the present invention, the compound of formula (XII) to be used as a starting material is 3,3-dimethyl glutaric hydride of the formula (II) and 1,4-dich of the formula (XIV) 4,4-dimethyl-1- (4-aminobutyl) -2,6-pyridine diol of Structural Formula (XV) which can be easily obtained by reacting aminobutane for 2 to 10 hours under reflux using a glacial acetic acid solvent.

Prepared by reaction with 1,2-dihaloethane in a suitable organic solvent in the presence or absence of basic condensates or by reaction with 2-haloethanol and then halogenated.

or

The reaction for obtaining the target compound of formula (I) by reacting the compound of formula (XII) and 2-aminopyrimidine, which is a feature of the present invention, is carried out in a suitable organic solvent in the presence or absence of a basic condensate.

Examples of the organic solvent include aromatic hydrogen carbonates such as benzene and toluene, alcohols such as methanol, butanol and amyl alcohol, dimethylformamide and acetonitrile, and examples of the basic condensate include sodium carbonate, potassium carbonate and hydrogen carbonate. Carbonates such as sodium and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metal alcoholates such as tartrium methylate and sodium ethylate, and tertiary amines such as pyridine and triethylamine. At this time, the ratio of the amount of the compound of the formula (XIII) to the amount of the compound of the formula (XII) is used in an equimolar amount or more, and the reaction is carried out at 40 ° C. to 150 ° C. for 2 to 10 hours.

In addition, the compound of the group (XII) is reacted with a known structural formula (IV) compound and diethanolamine to give 4,4-dimethyl [4- [di (2-hydroxy) -amino] butyl] -2,6- It may be prepared by obtaining piperidine dione and then reacting with a halogenating agent or by reacting a compound of formula (IV) with di (2-haloethyl) amine.

or

Hereinafter, the manufacturing method of the present invention will be described in detail with reference to Examples.

Example 1

Preparation of 4,4-dimethyl-1- (4-aminobutyl) -2,6-piperidine dione (XV).

26.4 g (0.3 mole) of 1,4-diaminobutane was dissolved in 200 ml of glacial acetic acid and 14.2 g (0.1 mole) of 3,3-dimethylglutaric anhydride was slowly added over 30 minutes, followed by 8 hours at reflux. To react. After the reaction is completed, the solvent is removed by concentration under reduced pressure, and the residue is extracted with chloroform and washed with water. Dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 15.5 g (73% yield) of the title compound.

Elemental Analysis: C ₁₁ H ₂₀ N ₂ O ₂

Theoretical value (%): C; 62.24, H; 9.50, N; 13.20

Found (%): C; 62.38, H; 9.36, N; 13.07

Example 2

Preparation of 4,4-dimethyl-1- [4- [di (2-chloroethyl) amino] butyl] -2,6-piperidine dione (XII)

To 4.3 g (0.02 mole) of 4,4-dimethyl-1- (4-aminobutyl) -2,6 piperidine dione 14.3 g (0.1 mole) of 1-bromo-2-chloroethanol 30 ml acetonitrile Suspension was added and 5.5 g (0.04 mol) of potassium carbonate was added and reacted under reflux for 10 hours. The reaction mixture is filtered, the solvent is concentrated under reduced pressure, extracted with chloroform and washed with water. Dehydration filtration with anhydrous magnesium sulfate and concentration under reduced pressure gave 4.4 g (64% yield) of the title compound.

Elemental division: C ₁₅ H ₂₆ C ₂ N ₂ O ₂

Theoretical value (%): C; 53.42, H; 7.77, N; 8.31

Found (%): C; 53.21, H; 7.80, N; 8.21

Example 3

Preparation of 4,4-dimethyl-1- [4- [di (2-chloroethyl) amino] butyl] -2,6-piperidine dione (XII)

4.3 g (0.02 mole) of 4,4-dimethyl-1- (4-aminobutyl) -2,6-piperidine dione and 12.5 g (0.01 mole) of 2-bromoethanol are suspended in 30 ml of acetonitrile. 5.5 g (0.04 mole) of potassium carbonate was added thereto and reacted for 15 hours under reflux.

After the reaction mixture was filtered and the solvent was removed under reduced pressure, 20 ml of benzene was added to the residue, 19 ml of pyridine was added, and 3 ml of thionyl chloride was slowly added, followed by reaction at room temperature for 5 hours. After the reaction was washed once with water, dehydrated with anhydrous magnesium sulfate, filtered and concentrated to give 4.9 g (72% yield) of the title compound.

Example 4

Preparation of 4,4-dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidine dione hydrochloride (I)

2.4 g (0.03 mole) of 3.4 g (0.01 mole) of 4,4-dimethyl-1- [4- [di- (2-clonethyl) -amino] butyl] -2,6-piperidine dione 2-aminopyrimidine and 2.8 g (0.02 mol) of potassium carbonate were suspended in 30 ml of amyl alcohol and reacted under reflux for 8 hours. Then 10 ml of 50% potassium carbonate solution was added, and the home mixture was concentrated under reduced pressure.

The obtained residue was extracted with benzene, washed with water, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 4.1 g of an oily substance. This was distilled off and 2.8g of base and (boiling point 210-230 degreeC, 0.01mmHg) were obtained.

Elemental _{analysis: C 19 H 29 N 5 O} 2 · HCI

Theoretical value (%): C; 57.64, H; 7.64, N; 17.69

Found (%): C; 57.61, H; 7.40, N; 17.60

IR (KBr): 1120, 1360, 1450, 1555, 1587, 1670, 1720, 2450, 2960 cm ^-1

NMR (DMSO-d6): 1.00 (6H, s), 1.60 (4H, m), 2.56 (4H, m), 3.09 (4H, m), 3.55 (6H, m), 4.67 (2H, bd, 13.3Hz ), 6.75 (1H, t, 4.6 Hz), 8.45 (2H, d, 4.6 Hz), 11.70 (1H, bs)

Claims (1)

4,4-dimethyl-1 [4- [di (2-chloroethyl) amino] butyl] -2,6-piperidine dione represented by Structural Formula (XII) and 2-aminopyri represented by Structural Formula (XII) Midine is reacted in the presence of a base to give 4,4-dimethyl-1 [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidine dione of formula (I). And a method for producing the hydrochloride.

Where X ₁ and X ₂ are chlorine, bromine and iodine, respectively.