CN100443473C - Synthetic method of 1-amino-3-(azacyclylalkyl)-2,4-imidazoledione - Google Patents

Abstract

A kind of synthetic method of 1-amino-3-(azacyclyl alkyl)-2,4-imidazole diketone, it is 1-benzylideneamino-Hitein alkali metal salt and α, ω-dihaloalkane hydrocarbon reaction to generate compound 1-benzylidene amino-3-(ω-halogenated hydrocarbon group)-2,4-imidazole dione, and then react with nitrogen heterocycle in an aprotic polar solvent under basic conditions to make The halogen atom is replaced by the nitrogen atom of the nitrogen heterocycle to obtain 1-benzylideneamino-3-(azacyclylalkyl)-2,4-imidazole dione, and finally the 1-benzylideneamino-3 -(Azacyclylalkyl)-2,4-imidazoledione is refluxed under acid catalysis, and the reaction solution is neutralized with alkali, concentrated to obtain 1-amino-3-(azacycyclylalkyl)-2, 4-Imidazoledione. Since all the reagents used in the present invention are cheap and easy to obtain, the operation is simple and easy, and at the same time, the yield is also high, which effectively improves the production efficiency and has great significance for reducing the production cost.

Description

Synthetic method of 1-amino-3-(azacyclylalkyl)-2,4-imidazoledione

technical field

The invention relates to a synthesis method of a pharmaceutical chemical intermediate 1-amino-2,4-imidazoledione derivative.

Background technique

After consulting a large number of documents, the synthetic methods of 1-amino-3-[4-(4-methyl-1-piperazine) butyl]-2,4-imidazoledione that have been reported so far are:

The reagents used in this method are expensive and the steps are long, the cost is high, and the yield is low, so it cannot be applied to production. And imidazole diketone compound intermediates are widely used in the pharmaceutical and chemical industries, therefore, it is extremely necessary to invent a simple and low-cost synthetic method.

Contents of the invention

The object of the present invention is to invent a kind of 1-amino-3-(azacycyclyl alkyl)-2,4-imidazole dione synthesis method which is simple, easy to implement and low in production cost.

The synthetic route of the present invention is as follows:

Technical scheme of the present invention is as follows:

A kind of synthetic method of 1-amino-3-(azacyclyl alkyl)-2,4-imidazoledione, it comprises the following steps:

Step 1. Making 1-benzylideneamino-2,4-imidazoledione into an alkali metal salt,

Step 2. 1-benzylideneamino-2,4-imidazole dione alkali metal salt prepared in step 1 is mixed with α, ω-dihaloalkane in N, N-dimethylformamide (DMF) at 40 React at ~80°C for 2 to 12 hours to generate compound 1-benzylideneamino-3-(ω-haloalkyl)-2,4-imidazoledione, the amount of reactant: 1-benzylideneamino-2,4 - The ratio of the amount of imidazole diketone alkali metal salt to α, ω-dihalogenated alkanes is 1: 2 to 1: 5

Step 3. The 1-benzylideneamino-3-(ω-halogenated alkyl)-2,4-imidazole diketone obtained in step 2 is then mixed with nitrogen heterocycle in an aprotic polar solvent and under basic conditions React at 60-86°C for 1.5-7 hours to replace the halogen atom with the nitrogen atom of the nitrogen heterocycle to obtain 1-benzylideneamino-3-(azacyclylalkyl)-2,4-imidazoledione, The amount of reactants: 1-benzylideneamino-3-(ω-halogenated alkyl)-2,4-imidazoledione and the ratio of nitrogen heterocyclic substances are 1:4～1:15

Step 4. reflux the 1-benzylideneamino-3-(azacyclylalkyl)-2,4-imidazoledione obtained in step 3 under acid catalysis, neutralize the reaction solution with alkali, concentrate, 1-Amino-3-(azacyclylalkyl)-2,4-imidazoledione is obtained.

In the above-mentioned synthetic method, in step 1, 1-benzylidene amino-2,4-imidazole dione can be reacted with an alcoholic solution of sodium hydroxide or potassium hydroxide to obtain 1-benzylidene amino-2,4- The imidazole diones are prepared as alkali metal salts.

In the above synthetic method, in step 2, the main chain of the α,ω-dihalogenated alkane can be 2-6 carbons.

In the above synthesis method, in step 2, the α,ω-dihaloalkane may be dibromoalkane or monobromomonochloroalkane. Preferred are dibromoalkanes.

In the above synthetic method, in step 3, the aprotic polar solvent may be acetonitrile, chloroform or N,N-dimethylformamide, preferably acetonitrile.

In the above synthesis method, in step 3, potassium carbonate or sodium carbonate can be used to neutralize the hydrogen halide released during the reaction.

In the above synthesis method, in step 4, the acid catalyst can be hydrochloric acid, sulfuric acid or strongly acidic ion exchange resin.

In the above-mentioned synthetic method, in step 4, when using a strong acidic ion exchange resin as a catalyst, after the reflux is completed, the reaction solution is filtered off the ion exchange resin and concentrated to obtain 1-amino-3-(azacyclylalkyl )-2,4-imidazoledione.

Since all the reagents used in the present invention are cheap and easy to obtain, the operation is simple and easy, and at the same time, the yield is also high, which effectively improves the production efficiency and has great significance for reducing the production cost.

Detailed ways

Embodiment 1.1-amino-3-[4-(4-methyl-1-piperazine) butyl]-2, the synthesis of 4-imidazole diketone

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 20 ml of ethanol was stirred, and refrigerated at 0°C. A precipitate was separated out to obtain 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(4-bromobutyl)-2,4-imidazoledione

Add 100 ml of DMF and 18.8 g (0.087 mol) of 1,4-dibromobutane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 60 ° C, and stir for 2 Hour. Concentration under reduced pressure gave 8.99 g of white powder. Yield: 92.0%.

3. Synthesis of 1-benzylideneamino-3-[4-(4-methyl-1-piperazine)butyl]-2,4-imidazoledione

Add 11.018g (0.11mol) of methylpiperazine to 7.5g (0.022mol) of 1-benzylideneamino-3-(4-bromobutyl)-2,4-imidazoledione, 150ml of acetonitrile, K ₂ CO ₃ 1.52g (0.011mol), reflux for 2hr. On cooling, a solid precipitated out. 7.11 g of white crystals were obtained by filtration. Yield: 90.6%.

4. Synthesis of 1-amino-3-[4-(4-methyl-1-piperazine)butyl]-2,4-imidazoledione

3.57 g (0.01 mol) of 1-benzylideneamino-3-[4-(4-methyl-1-piperazine) butyl]-2,4-imidazoledione was added to aqueous hydrochloric acid [hydrochloric acid: water (v/v)=1:10] 100ml, refluxed for 1 hour; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.63g of off-white prismatic crystals. mp: 96-98°C. Yield: 98.0%.

Example 2.1-amino-3-[3-(4-methyl-1-piperazine) propyl]-2, the synthesis of 4-imidazole dione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione sodium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 0.65 g of NaOH and 100 ml of ethanol was stirred for 0.5 hours, at 0°C Refrigerated, precipitated, and obtained 2.18 g of the product. Yield: 96.7%.

2. Synthesis of 1-benzylideneamino-3-(3-bromopropyl)-2,4-imidazoledione

Add 100ml of DMF and 4.04g (0.02mol) of 1,3-dibromopropane to 2.25g (0.01mol) of 1-benzylideneamino-2,4-imidazoledione sodium salt, heat to 80°C, and stir for 7 hours . Concentration under reduced pressure gave 3.07 g of white powder. Yield: 95.3%.

3. Synthesis of 1-benzylideneamino-3-[3-(4-methyl-1-piperazine)propyl]-2,4-imidazoledione

Add 8.0g (0.08mol) of methylpiperazine, 150ml of acetonitrile, K ₂ CO ₃ 1.38g (0.01mol), refluxed for 2 hours. On cooling, a solid precipitated out. 6.15 g of white crystals were obtained by filtration. Yield: 89.7%.

4. Synthesis of 1-amino-3-[3-(4-methyl-1-piperazine)propyl]-2,4-imidazoledione

Add 3.43 g (0.01 mol) of 1-benzylideneamino-3-[3-(4-methyl-1-piperazine) propyl]-2,4-imidazoledione in aqueous hydrochloric acid [hydrochloric acid: water (v/v)=1:10] 100ml, refluxed for 1 hour; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.51g of light yellow solid. mp: 46-48°C. Yield: 99.0%.

Example 3.1-amino-3-[2-(4-methyl-1-piperazine) ethyl]-2, the synthesis of 4-imidazole dione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and a solution prepared by adding 0.82 g of KOH and 100 ml of ethanol was stirred for 0.5 hours, at 0°C Refrigerated, precipitated, and obtained 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(2-bromoethyl)-2,4-imidazoledione

100 ml of DMF and 21.8 g (0.116 mol) of dibromoethane were added to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heated to 40° C., and stirred for 2 hours. Concentrate under reduced pressure to obtain 8.30 g of white powder. Yield: 92.6%.

3. Synthesis of 1-benzylideneamino-3-[2-(4-methyl-1-piperazine)ethyl]-2,4-imidazoledione

1-benzylideneamino-3-(4-bromobutyl)-2,4-imidazoledione 6.18g (0.02mol) was added to methylpiperazine 22.0g (0.22mol), acetonitrile 150ml, K ₂ CO ₃ 1.38g (0.01mol), refluxed for 2 hours. On cooling, a solid precipitated out. 6.27 g of white crystals were obtained by filtration. Yield: 95.3%.

4. Synthesis of 1-amino-3-[2-(4-methyl-1-piperazine)ethyl]-2,4-imidazoledione

Add aqueous hydrochloric acid to 3.29 g (0.01 mol) of 1-benzylideneamino-3-(4-hexahydropyridinebutyl)-2,4-imidazoledione [hydrochloric acid: water (v/v) = 1: 10] 100ml, refluxed for 2 hours; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.32g of yellow solid. mp: 40-42°C. Yield: 96.3%.

Example 4.1-amino-3-[4-(1-piperidine) butyl]-2, the synthesis of 4-imidazole dione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred for 0.5 hours, at 0°C Refrigerated, precipitated, and obtained 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(4-chlorobutyl)-2,4-imidazoledione

Add 120 ml of DMF and 17.0 g (0.10 mol) of 1-bromo-4-chlorobutane to 4.82 g (0.02 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, and heat to 80 ° C. Stir for 2 hours. Concentrate under reduced pressure to obtain 5.10 g of off-white powder. Yield: 87.2%.

3. Synthesis of 1-benzylideneamino-3-[4-(1-piperidinyl)butyl]-2,4-imidazoledione

Add 18.7g (0.22mol) of hexahydropyridine to 6.44g (0.022mol) of 1-benzylideneamino-3-(4-chlorobutyl)-2,4-imidazoledione, 150ml of acetonitrile, Na ₂ CO ₃ 1.17 g (0.011 mol), reflux for 1.5 hours. On cooling, a solid precipitated out. 6.67 g of light yellow solid was obtained by filtration. Yield: 88.7%.

4. Synthesis of 1-amino-3-[4-(1-piperidinyl)butyl]-2,4-imidazoledione

Add 100ml of sulfuric acid aqueous solution (1Mol/L) to 3.42g (0.01mol) of 1-benzylideneamino-3-[4-(1-piperidine)butyl]-2,4-imidazoledione, and reflux for 1 hours; neutralized with KOH and concentrated to obtain 2.48 g of light yellow prism crystals. mp: 58-60°C. Yield: 97.6%.

Example 5.1-amino-3-[3-(1-piperidinyl) propyl]-2, the synthesis of 4-imidazole dione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred for 0.5 hours, at 0°C Refrigerated, precipitated, and obtained 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(3-chloropropyl)-2,4-imidazoledione

Add 120 ml of DMF and 15.6 g (0.10 mol) of 1-bromo-3-chloropropane to 4.82 g (0.02 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 60 ° C, and stir for 2 Hour. Concentrate under reduced pressure to obtain 5.16 g of off-white powder. Yield: 92.5%.

3. Synthesis of 1-benzylideneamino-3-[3-(1-piperidinyl)propyl]-2,4-imidazoledione

Add 8.5g (0.10mol) of hexahydropyridine to 2.79g (0.01mol) of 1-benzylideneamino-3-(3-chloropropyl)-2,4-imidazoledione, 100ml of acetonitrile, Na ₂ CO ₃ 0.53 g (0.005mol), stirred and refluxed for 1.5 hours. On cooling, a solid precipitated out. 3.0 g of a yellowish solid was obtained by filtration. Yield: 91.5%.

4. Synthesis of 1-amino-3-[3-(1-piperidinyl)propyl]-2,4-imidazoledione

Add 100ml of aqueous sulfuric acid (Mol/L) to 3.28g (0.01mol) of 1-benzylideneamino-3-[3-(1-piperidinyl)propyl]-2,4-imidazoledione, and reflux for 2 hours; neutralized with KOH and concentrated to obtain 2.34 g of a yellow solid. mp: 44-46°C. Yield: 97.5%.

Example 6.1-amino-3-[2-(1-piperidine) ethyl]-2, the synthesis of 4-imidazole dione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03g (0.01mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100ml of absolute ethanol, and the solution prepared by adding 1.12g of KOH and 100ml of ethanol was stirred for 0.2 hours. Refrigerated, precipitated, and obtained 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(2-bromoethyl)-2,4-imidazoledione

100 ml of DMF and 21.8 g (0.116 mol) of dibromoethane were added to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heated to 60° C., and stirred for 2 hours. Concentrate under reduced pressure to obtain 8.30 g of white powder. Yield: 92.6%.

3. Synthesis of 1-benzylideneamino-3-[2-(1-piperidinyl)ethyl]-2,4-imidazoledione

Add 9.35g (0.11mol) of hexahydropyridine to 3.09g (0.01mol) of 1-benzylideneamino-3-(2-bromoethyl)-2,4-imidazoledione, 100ml of acetonitrile, Na ₂ CO ₃ 0.53 g (0.005mol), refluxed for 2.5 hours. On cooling, a solid precipitated out. 2.96 g of off-white solid was obtained by filtration. Yield: 94.3%.

4. Synthesis of 1-amino-3-[2-(1-piperidinyl)ethyl]-2,4-imidazoledione

Add 100ml of sulfuric acid aqueous solution (Mol/L) to 3.14g (0.01mol) of 1-benzylideneamino-3-[2-(1-piperidine)ethyl]-2,4-imidazoledione, and reflux for 1 hours; neutralized with KOH and concentrated to obtain 2.07 g of a yellow solid. mp: 38-40°C. Yield: 91.6%.

Example 7. Synthesis of 1-amino-3-[4-(1-tetrahydropyrrole) butyl]-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03g (0.01mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100ml of absolute ethanol, and the solution prepared by adding 1.12g of KOH and 100ml of ethanol was stirred for 0.2 hours. Refrigerated, precipitated, and obtained 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(4-bromobutyl)-2,4-imidazoledione

Add 200 ml of DMF and 18.8 g (0.087 mol) of 1,4-dibromobutane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 80°C, and stir for 2 Hour. Concentration under reduced pressure gave 8.99 g of white powder. Yield: 92.0%.

3. Synthesis of 1-benzylideneamino-3-[4-(1-tetrahydropyrrole)butyl]-2,4-imidazoledione 1-benzylideneamino-3-(4-bromobutyl) - 7.40 g (0.022 mol) of 2,4-imidazoledione was added with 17.0 g (0.24 mol) of tetrahydropyrrole, 150 ml of DMF, and 1.17 g (0.011 mol) of Na ₂ CO ₃ , and stirred at 80° C. for 1.5 hours. On cooling, a solid precipitated out. 6.47 g of light yellow solid was obtained by filtration. Yield: 89.7%.

4. Synthesis of 1-amino-3-[4-(1-tetrahydropyrrole)butyl]-2,4-imidazoledione

Add 3.28 g (0.01 mol) of 1-benzylideneamino-3-[4-(1-tetrahydropyrrole) butyl]-2,4-imidazoledione in aqueous hydrochloric acid [hydrochloric acid: water (v/v )=1:10] 100ml, refluxed for 1 hour; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.34g of off-white solid. mp: 87-89°C. Yield: 97.3%.

Example 8. Synthesis of 1-amino-3-[3-(1-tetrahydropyrrole)propyl]-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C. A precipitate was separated out to obtain 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(3-bromopropyl)-2,4-imidazoledione

Add 100ml of DMF and 4.04g (0.02mol) of 1,3-dibromopropane to 2.25g (0.01mol) of 1-benzylideneamino-2,4-imidazoledione sodium salt, heat to 60°C, and stir for 2 hours . Concentration under reduced pressure gave 3.07 g of white powder. Yield: 95.3%.

3. Synthesis of 1-benzylideneamino-3-[3-(1-tetrahydropyrrole)propyl]-2,4-imidazoledione

1-benzylideneamino-3-(3-bromopropyl)-2,4-imidazoledione 6.46g (0.02mol) add tetrahydropyrrole 17.0g (0.24mol), acetonitrile 150ml, Na ₂ CO ₃ 1.06 g (0.010mol), reflux for 1.5 hours. On cooling, a solid precipitated out. 5.76 g of light yellow solid was obtained by filtration. Yield: 91.7%.

4. Synthesis of 1-amino-3-[3-(1-tetrahydropyrrole)propyl]-2,4-imidazoledione

3.14 g (0.01 mol) of 1-benzylidene amino-3-[3-(1-tetrahydropyrrole) propyl]-2,4-imidazoledione was added to hydrochloric acid aqueous solution [hydrochloric acid: water (v/v )=1:10] 100ml, refluxed for 1 hour; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.22g of yellow solid. mp: 65-67°C. Yield; 98.3%.

Example 9. Synthesis of 1-amino-3-[2-(1-tetrahydropyrrole) ethyl]-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C. A precipitate was separated out to obtain 2.29 g of the product. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(2-bromoethyl)-2,4-imidazoledione

Add 220 ml of DMF and 21.8 g (0.116 mol) of dibromoethane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 80° C., and stir for 3 hours. Concentrate under reduced pressure to obtain 8.30 g of white powder. Yield: 92.6%.

3. Synthesis of 1-benzylideneamino-3-[2-(1-tetrahydropyrrole)ethyl]-2,4-imidazoledione 1-benzylideneamino-3-(2-bromoethyl) - 6.18g (0.02mol) of 2,4-imidazoledione was added with 21.3g (0.30mol) of tetrahydropyrrole, 150ml of acetonitrile, and 1.06g (0.01mol) of Na ₂ CO ₃ , stirred and refluxed for 2 hours. On cooling, a solid precipitated out. It was filtered off and recrystallized from acetonitrile to obtain 5.70 g of off-white solid. Yield: 95.1%.

4. Synthesis of 1-amino-3-[2-(1-tetrahydropyrrole)ethyl]-2,4-imidazoledione

Add 3.0 g (0.01 mol) of 1-benzylideneamino-3-[2-(1-tetrahydropyrrole) ethyl]-2,4-imidazoledione in aqueous hydrochloric acid [hydrochloric acid: water (v/v )=1:10] 100ml, refluxed for 2 hours; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.06g of brown-yellow solid. mp: 52-54°C. Yield: 97.5%.

Example 10. Synthesis of 1-amino-3-[4-(1-pyrrole)butyl]-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C to obtain Product 2.29g. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(4-bromobutyl)-2,4-imidazoledione

Add 220 ml of DMF and 18.8 g (0.087 mol) of 1,4-dibromobutane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 50 ° C, and stir for 2 Hour. Concentration under reduced pressure gave 8.99 g of white powder. Yield: 92.0%.

3. Synthesis of 1-benzylideneamino-3-[4-(1-pyrrole)butyl]-2,4-imidazoledione 1-benzylideneamino-3-(4-bromobutyl)-2 14.7 g (0.22 mol) of 1H-pyrrole, 150 ml of acetonitrile, and 1.17 g (0.011 mol) of Na ₂ CO ₃ were added to 7.40 g (0.022 mol) of 4-imidazoledione, and refluxed for 1.5 hours. On cooling, a solid precipitated out. 7.13 g of light yellow solid was obtained by filtration. Yield: 93.7%.

4. Synthesis of 1-amino-3-[4-(1-pyrrole)butyl]-2,4-imidazoledione

Add aqueous hydrochloric acid to 3.24 g (0.01 mol) of 1-benzylideneamino-3-[4-(1-pyrrole) butyl]-2,4-imidazoledione [hydrochloric acid: water (v/v) = 1:10] 100ml, refluxed for 1 hour; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.20g of yellow solid. mp: 95-97°C. Yield: 93.2%.

Example 11. Synthesis of 1-amino-3-[3-(1-pyrrole) propyl]-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C to obtain Product 2.29g. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(3-bromopropyl)-2,4-imidazoledione

Add 100ml of DMF and 4.04g (0.02mol) of 1,3-dibromopropane to 2.25g (0.01mol) of 1-benzylideneamino-2,4-imidazoledione sodium salt, heat to 80°C, and stir for 2 hours . Concentration under reduced pressure gave 3.07 g of white powder. Yield: 95.3%.

3. Synthesis of 1-benzylideneamino-3-[3-(1-pyrrole)propyl]-2,4-imidazoledione

1-benzylideneamino-3-(3-bromopropyl)-2,4-imidazoledione 6.46g (0.02mol) add 1H-pyrrole 16.0g (0.24mol), acetonitrile 150ml, Na ₂ CO ₃ 1.06 g (0.01mol), reflux for 1.5 hours. On cooling, a solid precipitated out. 5.75 g of light yellow solid was obtained by filtration. Yield: 92.7%.

4. Synthesis of 1-amino-3-[3-(1-pyrrole)propyl]-2,4-imidazoledione

Add aqueous hydrochloric acid to 3.14 g (0.01 mol) of 1-benzylideneamino-3-[3-(1-pyrrole) propyl]-2,4-imidazoledione [hydrochloric acid: water (v/v) = 1:10] 100ml, refluxed for 2 hours; neutralized with Na ₂ CO ₃ , concentrated to obtain 2.12g of yellow solid. mp: 76-78°C. Yield: 95.5%.

Example 12. Synthesis of 1-amino-3-[2-(1-pyrrole) ethyl]-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and a solution prepared by adding 1.12 g of KOH and 1.12 ml of ethanol was added, stirred, and refrigerated at 0°C to obtain Product 2.29g. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(2-bromoethyl)-2,4-imidazoledione

Add 220 ml of DMF and 21.8 g (0.116 mol) of dibromoethane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 80° C., and stir for 2 hours. Concentrate under reduced pressure to obtain 8.30 g of white powder. Yield: 92.6%.

3. Synthesis of 1-benzylideneamino-3-[2-(1-pyrrole)ethyl]-2,4-imidazoledione

1-benzylideneamino-3-(2-bromoethyl)-2,4-imidazoledione 6.18g (0.02mol) add 1H-pyrrole 20.1g (0.30mol), acetonitrile 150ml, Na ₂ CO ₃ 1.06 g (0.01mol), stirred and refluxed for 2 hours. On cooling, a solid precipitated out. 5.63 g of off-white solid was obtained by filtration. Yield: 95.1%.

4. Synthesis of 1-amino-3-[2-(1-pyrrole) ethyl]-2,4-imidazoledione

Add aqueous hydrochloric acid to 2.96 g (0.01 mol) of 1-benzylideneamino-3-[2-(1-pyrrole) ethyl]-2,4-imidazoledione [hydrochloric acid: water (v/v) = 1:10] 100ml was refluxed for 1 hour; neutralized with Na ₂ CO ₃ and concentrated to obtain 2.0 g of a brown-yellow solid. mp: 48-50°C. Yield: 96.2%.

Example 13. Synthesis of 1-amino-3-{4-[4-(3-trifluoromethoxyphenyl)-1-piperazine]butyl}-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C to obtain Product 2.29g. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(4-bromobutyl)-2,4-imidazoledione

Add 220 ml of DMF and 18.8 g (0.087 mol) of 1,4-dibromobutane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 40 ° C, stir about 2 hours. Concentration under reduced pressure gave 8.99 g of white powder. Yield: 92.0%.

3. Synthesis of 1-benzylideneamino-3-[4-(4-(3-trifluoromethoxyphenyl)-1-piperazine)butyl]-2,4-imidazoledione Add 4-(3-trifluoromethoxyphenyl)-1-piperazine 27.06g (0.11 mol), chloroform 250ml, K ₂ CO ₃ 1.52g (0.011mol), reflux for 2hr. On cooling, a solid precipitated out. 9.91 g of white crystals were obtained by filtration. Yield: 89.6%.

4. Synthesis of 1-amino-3-{4-[4-(3-trifluoromethoxyphenyl)-1-piperazine]butyl}-2,4-imidazoledione

5.03g (0.01mol ) was added aqueous hydrochloric acid [hydrochloric acid: water (v/v) = 1:10] 100ml, refluxed for 2 hours; neutralized with Na ₂ CO ₃ and concentrated to obtain 3.98g of light yellow solid. mp: 106-108°C. Yield: 96.0%.

Example 14. Synthesis of 1-amino-3-{3-[4-(4-methylphenyl)-1-piperazine]propyl}-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C to obtain Product 2.29g. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(3-bromopropyl)-2,4-imidazoledione

Add 100ml of DMF and 4.04g (0.02mol) of 1,3-dibromopropane to 2.25g (0.01mol) of 1-benzylideneamino-2,4-imidazoledione sodium salt, heat to 50°C, and stir for 3 hours . Concentration under reduced pressure gave 3.07 g of white powder. Yield: 95.3%.

3. Synthesis of 1-benzylideneamino-3-{3-[4-(4-methylphenyl)-1-piperazine]propyl}-2,4-imidazoledione 1-benzylideneamino -3-(3-bromopropyl)-2,4-imidazoledione 7.1g (0.022mol) was added 4-(4-methylphenyl)-1-piperazine 19.36g (0.11mol), chloroform 250ml, K ₂ CO ₃ 1.52g (0.011mol), reflux for 2hr. On cooling, a solid precipitated out. 7.61 g of white crystals were obtained by filtration. Yield: 82.6%.

4. Synthesis of 1-amino-3-[3-(4-(4-methylphenyl)-1-piperazine)propyl]-2,4-imidazoledione

Add 1-benzylideneamino-3-{3-[4-(4-methylphenyl)-1-piperazine]propyl}-2,4-imidazoledione 4.19g (0.01mol) Aqueous hydrochloric acid [hydrochloric acid: water (v/v) = 1:10] 100ml, refluxed for 2 hours; neutralized with Na ₂ CO ₃ , concentrated to obtain 3.28g of yellow solid. mp: 98-100°C. Yield: 99.1%.

Example 15. Synthesis of 1-amino-3-{2-[4-(2-methoxyphenyl)-1-piperazine]ethyl}-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C to obtain Product 2.29g. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(2-bromoethyl)-2,4-imidazoledione

Add 200 ml of DMF and 21.8 g (0.116 mol) of dibromoethane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 50°C, and stir for 2 hours. Concentrate under reduced pressure to obtain 8.30 g of white powder. Yield: 92.6%.

3. Synthesis of 1-benzylideneamino-3-{2-[4-(2-methoxyphenyl)-1-piperazine]ethyl}-2,4-imidazoledione 1-benzylidene Add 21.1g (0.11mol) of 4-(2-methoxyphenyl)-1-piperazine to amino-3-(2-bromoethyl)-2,4-imidazoledione 6.8g (0.022mol), chloroform 250ml, K ₂ CO ₃ 1.52g (0.011mol), reflux for 2hr. On cooling, a solid precipitated out. 9.26 g of white crystals were obtained by filtration. Yield: 89.6%.

4. Synthesis of 1-amino-3-{2-[4-(2-methoxyphenyl)-1-piperazine]ethyl}-2,4-imidazoledione

1-benzylideneamino-3-{2-[4-(2-methoxyphenyl)-1-piperazine]ethyl}-2,4-imidazoledione 4.21g (0.01mol) Add 100 ml of hydrochloric acid aqueous solution [hydrochloric acid: water (v/v) = 1:10] and reflux for 1 hour; neutralize with Na ₂ CO ₃ and concentrate to obtain 3.18 g of a yellow solid. mp: 67-69°C. Yield: 95.5%.

Example 16. Synthesis of 1-amino-3-[4-(1-cyclohexylimine)butyl]-2,4-imidazoledione

1. Synthesis of 1-benzylideneamino-2,4-imidazoledione potassium salt

2.03 g (0.01 mol) of 1-benzylideneamino-2,4-imidazoledione was dissolved in 100 ml of absolute ethanol, and the solution prepared by adding 1.12 g of KOH and 100 ml of ethanol was stirred and refrigerated at 0°C to obtain Product 2.29g. Yield: 95.1%.

2. Synthesis of 1-benzylideneamino-3-(4-bromobutyl)-2,4-imidazoledione

Add 250 ml of DMF and 18.8 g (0.087 mol) of 1,4-dibromobutane to 7.0 g (0.029 mol) of 1-benzylideneamino-2,4-imidazoledione potassium salt, heat to 60 ° C, and stir for about 2 hours. Concentration under reduced pressure gave 8.99 g of white powder. Yield: 92.0%.

3. Synthesis of 1-benzylideneamino-3-[4-(1-cyclohexylimino)butyl]-2,4-imidazoledione 1-benzylideneamino-3-(4-bromobutyl 10.9 g (0.11 mol) of hexahydroazepane (azepane), 150 ml of acetonitrile, and 1.52 g (0.011 mol) of K ₂ CO ₃ were added to 7.5 g (0.022 mol) of -2,4-imidazoledione, and refluxed for 2 hr. On cooling, a solid precipitated out. 7.09 g of white crystals were obtained by filtration. Yield: 90.6%.

4. Synthesis of 1-amino-3-[4-(1-cyclohexylimino)butyl]-2,4-imidazoledione

Add 100ml of water to 3.56g (0.01mol) of 1-benzylideneamino-3-[4-(1-cyclohexylimine)butyl]-2,4-imidazoledione, add sulfonic acid type strong acid ion 5 g of exchange resin was refluxed for 3 hours, filtered, and the filtrate was concentrated to obtain 2.58 g of light yellow solid. mp: 76-78°C. Yield: 96.3%.

Claims (9)

1. a kind of synthetic method of 1-amino-3-(azacyclyl alkyl)-2,4-imidazole diketone is characterized in that it comprises the following steps: Step 1. Making 1-benzylideneamino-2,4-imidazoledione into an alkali metal salt, Step 2. Mix the 1-benzylideneamino-2,4-imidazoledione alkali metal salt prepared in step 1 with α, ω-dihaloalkane in N,N-dimethylformamide at 40-80°C React for 2 to 12 hours to generate compound 1-benzylideneamino-3-(ω-haloalkyl)-2,4-imidazoledione, the amount of reactant: 1-benzylideneamino-2,4-imidazole dione The ratio of the amount of ketone alkali metal salt to α, ω-dihaloalkane is 1:1～1:5 Step 3. The 1-benzylideneamino-3-(ω-halogenated alkyl)-2,4-imidazole diketone obtained in step 2 is then mixed with nitrogen heterocycle in an aprotic polar solvent and under basic conditions React at 60-86°C for 1.5-7 hours to replace the halogen atom with the nitrogen atom of the nitrogen heterocycle to obtain 1-benzylideneamino-3-(azacyclylalkyl)-2,4-imidazoledione, The amount of reactant: 1-benzylideneamino-3-(ω-halogenated alkyl)-2,4-imidazole dione and the ratio of nitrogen heterocyclic substance amount is 1:4～1:15 Step 4. Reflux the 1-benzylideneamino-3-(azacyclylalkyl)-2,4-imidazoledione prepared in step 3 under acid catalysis, neutralize the reaction solution with alkali, and concentrate , to give 1-amino-3-(azacyclylalkyl)-2,4-imidazoledione. 2. synthetic method according to claim 1 is characterized in that: in step 1, with 1-benzylidene amino-2, the alcoholic solution reaction of 4-imidazole diketone and sodium hydroxide or potassium hydroxide makes 1 -Benzylideneamino-2,4-imidazoledione as an alkali metal salt. 3. The synthesis method according to claim 1, characterized in that: in step 2, the main chain of the α, ω-dihaloalkane is 2-6 carbons. 4. The synthesis method according to claim 1 or 3, characterized in that: in step 2, the α, ω-dihaloalkane is a dibromoalkane or a bromomonochloroalkane. 5. The synthetic method according to claim 4, characterized in that: the α, ω-dihaloalkane is a dibromoalkane. 6. The synthetic method according to claim 1, characterized in that: in step 3, the aprotic polar solvent is acetonitrile, chloroform or N,N-dimethylformamide. 7. synthetic method according to claim 1 is characterized in that: in step 3, described aprotic polar solvent is acetonitrile. 8. synthetic method according to claim 1 is characterized in that: in step 4, acid catalyst is hydrochloric acid, sulfuric acid or strongly acidic ion exchange resin. 9. the synthetic method according to claim 8 is characterized in that: in step 4, when using strongly acidic ion-exchange resin as catalyst, then after reflux finishes, reaction solution is filtered off ion-exchange resin, concentrates, obtains 1- Amino-3-(azacycyclylalkyl)-2,4-imidazoledione.