CN110590771A - A kind of [1,5-a]-pyridoimidazole-1-carbonitrile and its chemical synthesis method - Google Patents

Abstract

The invention relates to a chemical synthesis method of [1,5-a]-pyridoimidazole-1-carbonitrile. The method is as follows: starting from 2-fluoropyridine, [1,5-a]-pyridimidazole-1-carbonitrile is synthesized through five steps of ring closure, hydrolysis, acid halide, amidation and dehydration. The synthesis of compounds provides an efficient synthetic method.

Description

A kind of [1,5-a]-pyridoimidazole-1-carbonitrile and its chemical synthesis method

technical field

The invention relates to [1,5-a]-pyridoimidazole-1-carbonitrile and a chemical synthesis method thereof.

Background technique

Pyridoimidazoles have antiviral, antibacterial, antimicrobial, anti-fatigue and anti-anxiety effects, and are also widely used in the treatment of tumors, hypertension, gastric ulcers, and psychosis. As intermediates of fine chemical products, imidazopyridine compounds are widely used in catalysts, medicines, pesticides, and other fields. Therefore, the synthesis of imidazopyridine compounds is of great significance.

A kind of [1,5-a]-pyridoimidazole-1-carbonitrile is an important pharmaceutical intermediate, so the synthesis research of this compound has important practical significance.

Contents of the invention

The object of the present invention is to provide a compound that can be used as a pharmaceutical intermediate, namely: [1,5-a]-pyridoimidazole-1-carbonitrile, and provide its chemical synthesis method.

To achieve the above object, the technical scheme of the present invention is as follows:

A compound I, namely: [1,5-a]-pyridimidazole-1-carbonitrile, is characterized in that its molecular structure is as shown in Formula 1.

The chemical synthesis method of the compound I is characterized in that the compound I is synthesized through five-step reactions using 2-fluoropyridine as a raw material, as shown in formula 2.

The chemical synthesis method of the compound I is characterized in that it comprises the following synthesis steps:

S1. Under the protection of nitrogen, add sodium hydride to dimethyl sulfoxide, control the temperature at 0° C., add ethyl cyanoacetate, and stir for 0.5 h. Then add 2-fluoropyridine, control the reaction temperature, and react for 12 hours to obtain ethyl [1,5-a]-pyridimidazole-1-carboxylate;

S2. Add the ethyl [1,5-a]-pyridoimidazole-1-carboxylate obtained in step S1 into methanol, then add an aqueous solution of an inorganic base, control the reaction temperature and react for 3 hours, then add hydrochloric acid to obtain [1 ,5-a]-pyridoimidazole-1-carboxylic acid;

S3. Add [1,5-a]-pyridoimidazole-1-carboxylic acid obtained in step S2 into dichloromethane, then add thionyl chloride, and reflux for 3 hours to obtain [1,5-a]-pyridine And imidazole-1-carbonyl chloride;

S4. Control the ammonia water to a certain temperature, then add the [1,5-a]-pyridoimidazole-1-carbonyl chloride obtained in step S3, and stir for 3 hours to obtain [1,5-a]-pyridoimidazole-1 - Formamide;

S5. Add the [1,5-a]-pyridoimidazole-1-carboxamide obtained in step S4 into phosphorus oxychloride, and react at a certain temperature for 2 hours to obtain [1,5-a]-pyrido imidazole-1-carbonitrile.

Further, the reaction temperature of the step S1 is 30-70°C.

Further, the reaction temperature in step S2 is 30-100° C., and the inorganic base is one of sodium hydroxide, potassium carbonate, and potassium hydroxide.

Further, the certain temperature in the step S4 is -10-20°C.

Further, the certain temperature in the step S5 is 50-110°C.

The beneficial effect of the present invention is that: the chemical synthesis method of the present invention uses 2-fluoropyridine as a raw material to synthesize [1,5-a]-pyridimidazole-1-carbonitrile through five-step reactions. The method of the invention is simple and low in cost, and provides a solid foundation for mass production and follow-up research of this type of compound material.

Description of drawings

Figure 1 is the 1H-NMR spectrum of compound I prepared in Example 1.

Specific implementation method

The specific implementation mode below will describe in detail the specific implementation of the present invention. These specific implementation methods are only for description and are not used to limit the scope or implementation principle of the present invention. The protection scope of the present invention shall be determined by the claims, including obvious changes or changes made on this basis.

Example 1

Synthesis of S1, [1,5-a]-pyridoimidazole-1-carboxylic acid ethyl ester:

Add 96g of sodium hydrogen into a 5L four-neck flask, under mechanical stirring, control the system temperature at 0°C, add 2L of DMSO dropwise, after the dropwise addition, slowly add 271g of ethyl cyanoacetate, and stir for 30min after the dropwise addition, 194g 2-fluoropyridine was also slowly added dropwise into the system. After dropping, the mixture was stirred and reacted at 50°C for 12h. According to thin-layer chromatography, the reaction of the raw materials was complete, cooled to 0°C, and 100 mL of water was added dropwise to quench the reaction, 6 L of water was added, and ethyl acetate extracted 3 times (3×2 L), the organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain [1,5-a]-Pyridoimidazole-1-carboxylic acid ethyl ester 131g, yield 35%.

Synthesis of S2, [1,5-a]-pyridoimidazole-1-carboxylic acid:

In a 1L four-neck flask, 40g of [1,5-a]-pyridoimidazole-1-carboxylic acid ethyl ester was dissolved in 200mL of 12.6g of sodium hydroxide solution, and stirred at 70°C for 3h. According to thin-layer chromatography, the reaction of raw materials was complete, cooled to room temperature, adjusted to pH=3-4 with 12M hydrochloric acid, a large amount of solids precipitated, filtered, rinsed with water, and dried to obtain [1,5-a]-pyridimidazole- 32.8 g of 1-formic acid, the yield is 96.2%.

Synthesis of S3, [1,5-a]-pyridoimidazole-1-carbonyl chloride:

Add 120.5g of thionyl chloride to a 0.25L reaction flask and dissolve it in 0.1L of acetonitrile. Under magnetic stirring, add 32.8g of [1,5-a]-pyridoimidazole-1-carboxylic acid in batches, and heat Reflux for 3h. Thin-layer chromatography analyzed that the reaction of raw materials was complete, and concentrated to dryness to obtain [1,5-a]-pyridoimidazole-1-carbonyl chloride, which was directly carried out to the next step.

Synthesis of S4, [1,5-a]-pyridoimidazole-1-carboxamide:

Add the previous step [1,5-a]-pyridoimidazole-1-carbonyl chloride to a 1L four-necked flask and dissolve it in 0.2L methyl tert-butyl ether, and slowly add the above acid chloride solution to 400mL15 After adding ammonia water below ℃, continue to stir for 3h. Thin-layer chromatography analysis raw materials reacted completely, filtered, the filter cake was washed with water, dried, and the filtrate was extracted 8 times with dichloromethane (8 × 200mL), dried over anhydrous sodium sulfate, concentrated to dryness, and dried to obtain a total of 27g[1, 5-a]-pyridoimidazole-1-carboxamide, the yield was 83.1%.

Synthesis of S5, [1,5-a]-pyridoimidazole-1-carbonitrile:

Add 24g of [1,5-a]-pyridoimidazole-1-carboxamide into a 100mL three-necked flask, add 25mL of phosphorus oxychloride, and react at 110°C for 2h. According to thin-layer chromatography, the reaction of the raw materials was complete, the phosphorus oxychloride was concentrated, the residue was added to ice water, 500 mL of ethyl acetate was added, stirred for 0.5 h, filtered with a pad of silica gel, the filter cake was rinsed with ethyl acetate, separated, and the organic phase was dried , concentrated, and slurried with methyl tert-butyl ether to obtain 18g of [1,5-a]-pyridoimidazole-1-carbonitrile, the 1H-NMR spectrum of which is shown in Figure 1. The yield was 84.5%.

Example 2

Synthesis of S1, [1,5-a]-pyridoimidazole-1-carboxylic acid ethyl ester:

Add 96g of sodium hydrogen into a 5L four-neck flask, under mechanical stirring, control the temperature of the system at 0°C, add 2L of DMSO dropwise, after the dropwise addition, slowly add 271g of ethyl cyanoacetate dropwise, after the dropwise addition, stir for 30min, 194g 2-fluoropyridine was also slowly added dropwise into the system. After dropping, the mixture was stirred and reacted at 30°C for 12h. According to thin-layer chromatography, the reaction of raw materials was complete, cooled to 0°C, 100 mL of water was added dropwise to quench the reaction, 6 L of water was added, ethyl acetate extracted 3 times (3×2 L), the organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 123 g of ethyl [1,5-a]-pyridoimidazole-1-carboxylate, the yield was 32.9%.

Synthesis of S2, [1,5-a]-pyridoimidazole-1-carboxylic acid:

In a 1L four-necked flask, 40g of [1,5-a]-pyridoimidazole-1-carboxylic acid ethyl ester was dissolved in 200mL of 12.6g of sodium hydroxide solution, and stirred at 50°C for 3h. According to thin-layer chromatography, the reaction of raw materials was complete, cooled to room temperature, adjusted to pH=3-4 with 12M hydrochloric acid, a large amount of solids precipitated, filtered, rinsed with water, and dried to obtain [1,5-a]-pyridimidazole- 32.0 g of 1-formic acid, the yield is 93.9%.

Synthesis of S3, [1,5-a]-pyridoimidazole-1-carbonyl chloride:

Add 120.5g of thionyl chloride to a 0.25L reaction flask and dissolve it in 0.1L of acetonitrile. Under magnetic stirring, add 32.8g of [1,5-a]-pyridoimidazole-1-carboxylic acid in batches, and heat Reflux for 3h. Thin-layer chromatography analyzed that the reaction of raw materials was complete, and concentrated to dryness to obtain [1,5-a]-pyridoimidazole-1-carbonyl chloride, which was directly carried out to the next step.

Synthesis of S4, [1,5-a]-pyridoimidazole-1-carboxamide:

Add the previous step [1,5-a]-pyridoimidazole-1-carbonyl chloride to a 1L four-neck flask and dissolve it in 0.2L methyl tert-butyl ether, and slowly add the above acid chloride solution to 400mL under magnetic stirring After adding ammonia water below -10°C, continue stirring for 3 hours. Thin-layer chromatography analysis raw materials reacted completely, filtered, washed the filter cake with water, dried, and the filtrate was extracted 8 times with dichloromethane (8 × 200mL), dried over anhydrous sodium sulfate, concentrated to dryness, and dried to obtain a total of 21g[1, 5-a]-pyridoimidazole-1-carboxamide, the yield was 64.6%.

Synthesis of S5, [1,5-a]-pyridoimidazole-1-carbonitrile:

Add 24g of [1,5-a]-pyridoimidazole-1-carboxamide into a 100mL three-necked flask, add 25mL of phosphorus oxychloride, and react at 80°C for 2h. According to thin-layer chromatography, the reaction of the raw materials was complete, the phosphorus oxychloride was concentrated, the residue was added to ice water, 500 mL of ethyl acetate was added, stirred for 0.5 h, filtered with a pad of silica gel, the filter cake was rinsed with ethyl acetate, separated, and the organic phase was dried , concentrated, and beat with methyl tert-butyl ether to obtain 16 g of [1,5-a]-pyridoimidazole-1-carbonitrile with a yield of 75.1%.

Example 3

Synthesis of S1, [1,5-a]-pyridoimidazole-1-carboxylic acid ethyl ester:

Add 96g of sodium hydrogen into a 5L four-neck flask, under mechanical stirring, control the system temperature at 0°C, add 2L of DMSO dropwise, after the dropwise addition, slowly add 271g of ethyl cyanoacetate, and stir for 30min after the dropwise addition, 194g 2-fluoropyridine was also slowly added dropwise into the system. After dropping, the mixture was stirred and reacted at 70°C for 12h. According to thin-layer chromatography, the reaction of the raw materials was complete, cooled to 0°C, and 100 mL of water was added dropwise to quench the reaction, 6 L of water was added, and ethyl acetate extracted 3 times (3×2 L), the organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain [1,5-a]-Pyridoimidazole-1-carboxylic acid ethyl ester 133g, yield 35.5%.

Synthesis of S2, [1,5-a]-pyridoimidazole-1-carboxylic acid:

In a 1L four-neck flask, 40g of [1,5-a]-pyridoimidazole-1-carboxylic acid ethyl ester was dissolved in 200mL of 12.6g of sodium hydroxide solution, and stirred at 100°C for 3h. According to thin-layer chromatography, the reaction of raw materials was complete, cooled to room temperature, adjusted to pH=3-4 with 12M hydrochloric acid, a large amount of solids precipitated, filtered, rinsed with water, and dried to obtain [1,5-a]-pyridimidazole- 33.2 g of 1-formic acid, the yield was 97.4%.

Synthesis of S3, [1,5-a]-pyridoimidazole-1-carbonyl chloride:

Add 120.5g of thionyl chloride to a 0.25L reaction flask and dissolve it in 0.1L of acetonitrile. Under magnetic stirring, add 32.8g of [1,5-a]-pyridoimidazole-1-carboxylic acid in batches, and heat Reflux for 3h. Thin-layer chromatography analyzed that the reaction of raw materials was complete, and concentrated to dryness to obtain [1,5-a]-pyridoimidazole-1-carbonyl chloride, which was directly carried out to the next step.

Synthesis of S4, [1,5-a]-pyridoimidazole-1-carboxamide:

Add the previous step [1,5-a]-pyridoimidazole-1-carbonyl chloride to a 1L four-necked flask and dissolve it in 0.2L methyl tert-butyl ether, and slowly add the above acid chloride solution to 400mL5 under magnetic stirring. After adding ammonia water below ℃, continue to stir for 3h. Thin-layer chromatography analysis raw materials reacted completely, filtered, washed the filter cake with water, dried, and the filtrate was extracted 8 times with dichloromethane (8 × 200mL), dried over anhydrous sodium sulfate, concentrated to dryness, and dried to obtain a total of 30g[1, 5-a]-Pyridoimidazole-1-carboxamide, the yield is 92.1%.

Synthesis of S5, [1,5-a]-pyridoimidazole-1-carbonitrile:

Add 24g of [1,5-a]-pyridoimidazole-1-carboxamide into a 100mL three-necked flask, add 25mL of phosphorus oxychloride, and react at 50°C for 2h. According to thin-layer chromatography, the reaction of the raw materials was complete, the phosphorus oxychloride was concentrated, the residue was added to ice water, 500 mL of ethyl acetate was added, stirred for 0.5 h, filtered with a pad of silica gel, the filter cake was rinsed with ethyl acetate, separated, and the organic phase was dried , concentrated, and beat with methyl tert-butyl ether to obtain 13 g of [1,5-a]-pyridoimidazole-1-carbonitrile with a yield of 61%.

Claims (7)

1. A compound I, namely: [1,5-a ] -pyridylimidazole-1-carbonitrile, which is characterized in that the molecular structural formula is shown as formula 1.

2. The chemical synthesis method of the compound I as claimed in claim 1, wherein 2-fluoropyridine is used as a raw material to synthesize the compound I through five-step reaction, as shown in formula 2.

3. The chemical synthesis process of compound i according to claim 2, comprising the following synthesis steps:

s1, under the protection of nitrogen, adding sodium hydride into dimethyl sulfoxide, controlling the temperature at 0 ℃, adding ethyl cyanoacetate, and stirring for 0.5 h. Then adding 2-fluoropyridine, controlling the reaction temperature, and reacting for 12h to obtain [1,5-a ] -pyridylimidazole-1-ethyl formate;

s2, adding the [1,5-a ] -pyridoimidazole-1-ethyl formate obtained in the step S1 into methanol, then adding an aqueous solution of an inorganic base, controlling the reaction temperature to react for 3 hours, and then adding hydrochloric acid to obtain [1,5-a ] -pyridoimidazole-1-formic acid;

s3, adding the [1,5-a ] -pyridylimidazole-1-formic acid obtained in the step S2 into dichloromethane, then adding thionyl chloride, and refluxing for 3 hours to obtain [1,5-a ] -pyridylimidazole-1-formyl chloride;

s4, controlling ammonia water to a certain temperature, adding the [1,5-a ] -pyridylimidazole-1-formyl chloride obtained in the step S3, and reacting for 3 hours under stirring to obtain [1,5-a ] -pyridylimidazole-1-formamide;

s5, adding the [1,5-a ] -pyridylimidazole-1-formamide obtained in the step S4 into phosphorus oxychloride, reacting for 2 hours at a certain temperature, and reacting to obtain [1,5-a ] -pyridylimidazole-1-carbonitrile.

4. A process for the chemical synthesis of compound i according to claim 3, characterized in that: the reaction temperature of the step S1 is 30-70 ℃.

5. A process for the chemical synthesis of compound i according to claim 3, characterized in that: the reaction temperature of the step S2 is 30-100 ℃, and the inorganic base is one of sodium hydroxide, potassium carbonate and potassium hydroxide.

6. A process for the chemical synthesis of compound i according to claim 3, characterized in that: the certain temperature of the step S4 is-10-20 ℃.

7. A process for the chemical synthesis of compound i according to claim 3, characterized in that: the certain temperature of the step S5 is 50-110 ℃.