SU1836365A3 - Method for obtaining n-(1-piperazinyl)butylglutarimidines - Google Patents

Description

The invention relates to a method for producing derivatives of 1-aryl-, hetarylpiperazines, specifically 1 \ 1- (1-piperazinyl) butylglutarimides of the formula (1)

where Ri is aryl, hetaryl

R2 - H, alkyl

R3 is N. alkyl either

These compounds have pronounced psychotropic activity and is a pharmaceutical preparation with anxiolytic action.

A known method of producing N- (1-nnnerazinyl) butylglutarimides, according to which

3,3-disubstituted 4-bromobutylglutarimides (V) are prepared as follows

And ^r about

GNCHON

1836365 AZ

VZ to, Λ

X ”,, Br - = - = ► ν-Λ _γ one of them Busp

POH (R, 4 _{Rj =} ) ^

Acids (II) are first converted to anhydrides (III), and then the corresponding imides (IV) are obtained by boiling in an aqueous ammonia solution, they are alkylated with 1,4-dibromobutane and converted to 4-bromobutyl derivatives (V). Reaction of 1-aryl- or hetarylpiperazine (VI) with 4-bromobutylglutarimide-5 mid (V) yields the corresponding Y- (1-piperazinyl) butylglutarimides (I).

This method is selected as a prototype.

In accordance with the prototype N- (1-nnne-Yu rasinil) butylglutarimide receive in 4 stages:

stage: obtaining 3-methyl-3-propylglutaric anhydride (III: Ra = CH3. From = C3H?). 70 g (0.37 mol) of 3-methyl-3-propylglutaric acid are dissolved in 110 ml of acetic anhydride and carefully refluxed for 4 hours. The solution is concentrated to a dark oil, which is distilled at a temperature of 111 ° C and a pressure of 0, 1 mm Tg, getting 53.2 g (yield 84.5%). When standing, the colorless anhydride syrup crystallizes into a white solid.

stage: obtaining 3-methyl-3-propylglutarimide (I V.R2 = CH3, R3 = C3H7). 10 g (0.06 mol) of 3-methyl-3-propylglutaric anhydride are added in small portions to 120 ml of concentrated ammonia. After addition, the mixture was carefully refluxed and stirred for 4 hours. After cooling the reaction mixture, the yellow oil precipitated and solidified in the form of a glass. After crystallization from isopropyl alcohol, 8 g (80% yield) of crude product (IV) with mp. = 110-112 ° C.

? 3 / Phase-: obtaining TS4-bromobutyl) -3metil-3-propilglutarimida (V: R2 = CH, R ₃ = C ₃ H7). A mixture of 7-methyl-3-propylglutarimide (25 g, 0.15 mol), 1,4-dibromobutane (33 * 5 g, 0.15 mol) and potash (40.6 g, 0.29 mol) was stirred for 16 hours in 250 ml of boiling acetonitrile. Inorganic substances are separated by filtration, the filtrate is concentrated to an oily state. and then distilled at a temperature of 165-190 ° C and a pressure of 0.09 mm RT.article receiving 42.5 g (95% yield).

stage: obtaining 3-methyl-3-propyl1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] buK-b \ tyl] glutarimide (1 Lg = CH3, R ₃ =

C3H7). A mixture of Y- (4-bromobutyl) -3-methyl-3propylglutarimide (5 g. 0.016 mol) * 1- (2-pyrimidinyl) piperazine (2.62 g, 0.016 mol) potash (6.6 g, 0.048 mol) Potassium iodide (0.5 g) was stirred in 200 ml of boiling acetonitrile for approximately 18 hours. The reaction mixture was filtered and concentrated in vacuo to give an oil, which was purified as dihydrochloride. After recrystallization from isopropyl alcohol, 5 g of product are obtained (70% yield) with T _mp =

S = 188-204 ° C.

The disadvantages of the prototype are the complexity due to the multi-stage method and the multiplicity of operations for the isolation and purification of 10 intermediate substances, as well as the relatively low yield of target products.

The method is described by the following scheme:

.V-COtHffl ⁰ »

^Vg ~ n ^OgN

about.

; κ, -ν kn O ^ NhHW ^R? about ν

The proposed method is carried out 25 as follows. The corresponding glutaric acid is dissolved in aqueous ammonia and evaporated to dryness. The solid residue is maintained at 140-150 ° C for 5-6 hours and cooled. The resulting glutarimide 30 (IV) was recrystallized from isopropanol. Then, 1,4dibromobutane and potash were added to glutarimide (IV), stirred for 16 hours in boiling acetonitrile, the filtrate was concentrated to an oily state, distilled under reduced pressure to obtain (V). Then it is mixed with 1- (2-pyimidinyl) piperazine, sodium hydroxide, crown ether in benzene and boiled with stirring for 12 hours. The filtrate 40 is evaporated and recrystallized from isopropanol, obtaining the target product 1. The proposed method for producing I- (1-piperazinyl ) of butylglutarimides of formula I allows us to simplify and reduce the time of 45 synthesis to 31-32 hours from 41-42 hours while increasing the yield of target products from 45 to 60%. The inventive method is illustrated by the following example.

PRI me R 1. Z-methyl-Z-propyl N-4-4- (250 pyrimidinyl) -1-piperazinyl butyl glutarimide receive in 3 stages:

stage: obtaining 3-methyl-3tpropylglutarimide (IV: R2 = CH ₃ , R ₃ = C3H7). 86.6 g (0.46 mol) of 3-methyl-3-poplglutaric acid are dissolved in 130 ml (1.9 mol) of 28% aqueous ammonia and evaporated to dryness. The solid residue is maintained at 140-150 ° C in an oil bath for 5-6 hours and then cooled. The hardened residue was recrystallized from isopropanol, pol. 1836365, accounting for 68.5 g (88% yield) of the product mp. 110112 ° C.

Stage II: obtaining 1 \ 1- (4-bromobutyl) -3methyl-3-propylglutarimide (V: R ₂ = CH3, R3 = C3H7). A mixture of 7-methyl-3-propylglutarimide (25.4 g, 0.15 mol), 1,4-dibromobutane (32.4 g, 0.15 mol) and potash (40.0 g, 0.29 mol) was stirred for 16 hours in 250 ml of boiling acetonitrile. Inorganic substances are separated by filtration, the filtrate is concentrated to an oily state, and then distilled at a temperature of 184-200 ° C and a pressure of 0.1 mm Hg to obtain g (92% yield).

Stage Ill: Preparation of W-methyl-W-propilM- [4- (4- (2-pyrimidinyl) -1-piperazinyl) bu ⁷ til1glutarimida (1:? Ri = - \, R ₂ = CH, R3 = nSN3N7). A mixture of M- (4-bromobutyl) -3-methyl-3propylglutarimide (24.3 g, 0.08 mol), 1- (2pyrimidinyl) piperazine (13.1 g, 0.08 mol), 9.6 g (0 24 mol) of sodium hydroxide, 2.02 g (0.01 mol) of 15-crown-5 in 250 ml of benzene is boiled with stirring for 10 hours; The reaction mixture was filtered, evaporated in vacuo, 200 ml of water was added, the oily precipitate formed was separated and purified as dihydrochloride.

After recrystallization from isopropanol, 27.6 g of product are obtained (75% yield) with mp. = 187-203 ° C.

Similarly receive:

3-Ethyl-3-methyl-L1- [4- (4- (2-pyrimidinyl) -1-piperazinyl] butyl] glutarimide hydrochloride, mp 196-197 ° C.

3.3- Tetramethylene-I- [4- [4- (2-pyrimidyl nyl) -1-piperazinyl] butyl] glutarimide hydrochloride mp. = 206 ~ 207 ° C.

3.3- Tetramethylene-B- [4- [4-phenyl-1-piperazinyl] butyl] glutarimide hydrochloride mp. = 218-220 °.

3.3- Tetramethylene-1CH- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] glutarimide hydrochloride mp. "172-174 ° C.

3.3- Tetramethylene-M- (4- [4- (o-methoxyphenyl) -1-piperazinyl] butyl] glutarimide dihydrochloride Mp = 172-175 ° C.

The proposed method for the production of N- (1 piperazinyl) butyl glutarimides has the following advantages: simplification of the synthesis due to the process in 3 stages <instead of four; acceleration of synthesis to 3132 hours, instead of 41-42 hours, increasing the yield of the target product from 45 to 60%.

Claims (1)

15 claims The method of obtaining Sch1-piperazinyl) butylglutarimides of General formula I 25 where Ri is aryl or hetaryl, R ₂ and R3 are hydrogen or alkyl, or R ₂ + R3 together form% CH ₂ ) 4-, starting from the corresponding glutaric acid by converting it to imide followed by alkylation of the resulting 4-bromobutylglutarimide 1-aryl or 1-hetarylpiperazine when heated in an organic solvent in the presence of an alkaline agent, characterized in that 35, the conversion to imide is carried out by treating glutaric acid with an aqueous ammonia solution, evaporating and maintaining the residue at 100-150 ° С, and 4-bromobutylglutarimide is treated in the presence of crown ether using an aromatic hydrocarbon as an organic solvent and an alkali as an alkaline agent.