NL2030537B1 - Method for synthesizing of imidazo[1,2-a] pyridine-3-formic acid - Google Patents

Abstract

The present disclosure relates to the field of organic synthesis, and more particularly to a method for synthesizing imidazo[l,2—a] pyridine—3—formic acid. The method comprises the following steps: enabling N,N—dimethylformamide dimethylacetal to react with 2— aminopyridine at 40—100°C for 2 to 8 hours to obtain an N,N— dimethyl—N’—2—pyridinecarboxamidine intermediate, enabling the intermediate to react with ethyl bromoacetate at 50—l60°C, and carrying out recrystallization to obtain a pure product; carrying out a hydrolysis reaction on imidazo[l,2—a] pyridine—3—ethyl formate for l to 5 hours in a certain solvent, and after the reaction is completed, carrying out hydrochloric acid neutralizing, filtering, water washing and drying to directly obtain a pure product of imidazo[l,2—a] pyridine—3—formic acid. The method is easy in availableness of reaction raw materials, reasonable in price, gentle in reaction condition, easy to operate, easy to control and simple in post—treatment, and in addition, the product quality obtained is stable, and the product purity is high.

Description

P937/NLpd METHOD FOR SYNTHESIZING OF IMIDAZO[1,2-A] PYRIDINE-3-FORMIC ACID

TECHNICAL FIELD The present disclosure relates to the field of organic syn- thesis, and more particularly to a method for synthesizing imid- azo[1,2-a] pyridine-3-formic acid.

BACKGROUND ART Imidazo[l,2-a] pyridine-3-formic acid is an important inter- mediate for organic synthesis, which is mainly applied to medical intermediates, organic synthesis and organic solvents, and also applied to aspects such as dye production, pesticide production and spices. Conventional preparation of imidazo[1,2-a] pyridine-3-formic acid has the following defects: (1) A large number of byproducts are produced, resulting in a dark product color and difficulties in refining and purification. Even after multiple times of recrystallization with organic sol- vents, the quality still cannot meet high requirements, and re- peated crystallization results in a low product yield, increased cost, and tedious operations. (2) A chemical reduction method used has serious equipment corrosion and environment pollution, and thus it is restricted from development at present. (3) Raw materials are limited in source, high in price and complicated to operate. {4} A noble metal catalyst needs to be used, so that the preparation cost is increased. All above problems all need to be solved.

SUMMARY Aiming at solving defects of the prior art, the present dis- closure provides a method for synthesizing imidazo[1,2-a] pyri- dine-3-formic acid. The synthesis method is simple to operate, high in yield and applicable to laboratory and industrial produc-

tion.

The present disclosure is achieved through the following technical solution: A method for synthesizing imidazo[1,2-a] pyridine-3-formic acid, comprising the following steps: {1) preparing imidazo[1,2-a] pyridine-3-ethyl formate: ena- bling N,N-dimethylformamide dimethylacetal as both a solvent and a reaction raw material to react with 2-aminopyridine at 40-100°C for 2-8 hours to obtain an N,N-dimethyl-N’-2-pyridinecarboxamidine intermediate, enabling the intermediate which does not need to be purified to react with ethyl bromoacetate at 50-160°C for 3-15 hours in a certain solvent under the action of an alkali, after the reaction is completed, cooling to a room temperature, extract- ing with ethyl acetate, washing with water and a saline solution, drying with anhydrous sodium sulfate, carrying out rotary evapora- tion concentration to obtain a crude product of imidazo[1,2-a] pyridine-3-ethyl formate, and recrystallizing the crude product to obtain a pure product; and (2) preparing imidazo[1,2-a] pyridine-3-formic acid: under the action of the alkali, carrying out a hydrolysis reaction on the imidazo[1,2-a] pyridine-3-ethyl formate for 1-5 hours in a certain solvent, and after the reaction ends, carrying out neu- tralizing with hydrochloric acid, filtering, water washing and drying to directly obtain a pure product of imidazo[1,2-a] pyri- dine-3-formic acid.

Reactions are as follows: Oo (XL DMF-DMA Si ot N™ “NH, NZ SNASNT base solvent | AN ~_N o OH © o According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, the alkali in the step (1) is at least one of potassium bicarbonate, potassium carbonate, sodium bicarbonate and sodium carbonate.

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, the solvent in the step (1) is at least one of dioxane, toluene and N,N- dimethylformamide.

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, a mixed solution of n-hexane and ethyl acetate in a volume ratio of 1: 1 is adopted for recrystallization in the step (1).

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, the molar ratio of N,N-dimethylformamide dimethylacetal to 2-aminopyridine to the alkali to ethyl bromoacetate in the step (1) is (2.5-3.5): 1: (1-

2.5): (1-2.5).

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, the hydrolysis temperature in the step (2) is 20-80°C.

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, , the solvent in the step (2) is a mixture of methanol or ethanol and water.

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, the alkali in the step (2) is at least one of sodium hydroxide, potassium hy- droxide and lithium hydroxide.

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, the concentra- tion of hydrochloric acid in the step (2) is 30%.

According to the method for synthesizing the imidazo[1,2-a] pyridine-3-formic acid in the present disclosure, the amount of the imidazo[1,2-a] pyridine-3-ethyl formate to the alkali in the step (2) is 1: (1-2.5).

The present disclosure has the beneficial effects that the method is easy in reaction raw material obtaining, reasonable in price, gentle in reaction condition, easy to operate, easy to con- trol and simple in post-treatment, and in addition, is stable in product quality and high in purity.

DETAILED DESCRIPTION OF THE EMBODIMENTS Example 1 80 mL (71.7 g) of N,N-dimethylformamide dimethylacetal as both a solvent and a reaction raw material was taken to react with 2-aminopyridine (18.8 g, 200 mmol) at 40°C for 5 hours to obtain an N,N-dimethyl-N’-2-pyridinecarboxamidine intermediate after the re- action ended. Rotary evaporation was carried out to remove exces- sive N,N-dimethylformamide dimethylacetal, 120 mL (114 g) of N,N- dimethylformamide (DMF), NaHCO; {25.2 g, 300 mmol) and ethyl bromo- acetate (50.1 g, 300 mmol) were added to react for 10 hours at 50°C. After the reaction ended, the mixture was cooled to a room temperature, and 600 mL of water and 200 mL of ethyl acetate were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3*200 mL), the or- ganic phases were combined, washed with water (2*150 mL), washed with 200 mL of a saturated saline solution, dried with anhydrous Na:S0,, and filtered. The filtrate was concentrated to obtain a crude product of imidazo[1,2-a] pyridine-3-ethyl formate, and the crude product was recrystallized with a mixed solution of n-hexane and ethyl acetate in a ratio of 1: 1 (volume ratio} to obtain 30.6 g of pure product. The yield was 80.5%, the melting point was:

49.6-51.5°C, 1HNMR (400 MHz, CDCl3) &: 9.31 (d, J=6.8Hz, 1H), 8.31 (s,1H), 7.74 (d, J=9.2Hz, 1H), 7.41 (t,J= 7.2Hz, 1H), 7.05 (t,J=6.8Hz, 1H) 4.42 (gq,J=7.2Hz, 2H), 1.42 (t,J=7.2Hz, 3H).

The imidazo[1,2-a] pyridine-3-ethyl formate (19.0 g, 100 mmol) and 100 mL of methanol were added to a 250 mL single-mouth flask. Sodium hydroxide (6.0 g, 150 mmol) was dissolved to 10 mL of water, added to a reaction flask, and stirred for 2 hours at 20°C. After the reaction ended, neutralization was carried out with 30% hydrochloric acid till the pH value was 5, suction filtration was carried out, and a filter cake was washed with a small amount of water, and was dried to obtain 10.3 g of a pure product of im- idazo[1,2-a] pyridine-3-formic acid. The yield was 63.6%, and the melting point was 196-197°C, 1HNMR (400MHz, CDCl;) 3:10.88 (s, 1H),

9.33 (d, J=7.2Hz, 1H), 8.30 (s,1lH), 7.72 (d, J=9.2Hz, 1H), 7.44 (t,J=8.0Hz, 1H), 7.10 (t,J=7.2Hz, 1H).

Example 2 80 mL (71.7 g) of N,N-dimethylformamide dimethylacetal as both a solvent and a reaction raw material was taken to react with 2-aminopyridine (18.8 g, 200 mmol) at 40°C for 5 hours to obtain an 5 N,N-dimethyl-N’-2-pyridinecarboxamidine intermediate after the re- action ended. Rotary evaporation was carried out to remove exces- sive N,N-dimethylformamide dimethylacetal, 120 mL (125 g) of diox- ane, NaHCO; (20.8 g, 150 mmol) and ethyl bromoacetate (50.1 g, 300 mmol) were added to react for 10 hours at 80°C. After the reaction ended, the mixture was cooled to a room temperature, and 600 mL of water and 200 mL of ethyl acetate were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3*200 mL), the organic phases were combined, washed with water (2*150 mL), washed with 200 mL of a saturated saline solution, dried with anhydrous Na:S0,, and filtered. The filtrate was concentrated to obtain a crude product of imid- azo[1,2-a] pyridine-3-ethyl formate, and the crude product was re- crystallized with a mixed solution of n-hexane and ethyl acetate in a ratio of 1: 1 (volume ratio) to obtain 21.6 g of pure prod- uct. The yield was 56.8%.

The imidazo[1,2-a] pyridine-3-ethyl formate (26.7g, 100 mmol) and 100 mL of methanol were added to a 250 mL single-mouth flask. Sodium hydroxide (8.4 g, 150 mmol) was dissolved to 10 mL of wa- ter, added to a reaction flask, and stirred for 2 hours at 40°C.

After the reaction ended, neutralization was carried out with 30% hydrochloric acid till the pH value was 4, suction filtration was carried out, and a filter cake was washed with a small amount of water, and was dried to obtain 11.1 g of a pure product of imid- azo[l,2-a] pyridine-3-formic acid. The yield was 68.6%.

Example 3 80 mL of N,N-dimethylformamide dimethylacetal as both a sol- vent and a reaction raw material was taken to react with 2- aminopyridine (18.8 g, 200 mmol) at 60°C for 5 hours to obtain an N,N-dimethyl-N’-2-pyridinecarboxamidine intermediate after the re- action ended. Rotary evaporation was carried out to remove exces- sive N,N-dimethylformamide dimethylacetal, 120 mL (103 g) of tolu-

ene, triethylamine (30.3g, 300 mmol) and ethyl bromoacetate (50.1 g, 300 mmol) were added to react for 8 hours at 100°C.

After the reaction ended, the mixture was cooled to a room temperature, and 600 mL of water and 200 mL of ethyl acetate were added for extrac- tion.

The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3*200 mL), the organic phases were combined, washed with water (2*150 mL), washed with 200 mL of a saturated saline solution, dried with anhydrous Na:S04, and fil- tered.

The filtrate was concentrated to obtain a crude product of imidazo[1,2-a] pyridine-3-ethyl formate, and the crude product was recrystallized with a mixed solution of n-hexane and ethyl acetate in a ratio of 1: 1 (volume ratio) to obtain 24.0 g of pure prod- uct.

The yield was 63.1%. The imidazo[1,2-a] pyridine-3-ethyl formate (19.0 g, 100 mmol) and 100 mL of methanol were added to a 250 mL single-mouth flask.

Sodium hydroxide (6.0 g, 150 mmol) was dissolved to 10 mL of water, added to a reaction flask, and stirred for 2 hours at 40°C.

After the reaction ended, neutralization was carried out with 30% hydrochloric acid till the pH value was 4, suction filtration was carried out, and a filter cake was washed with a small amount of water, and was dried to obtain 10.5 g of a pure product of im- idazo[1,2-a] pyridine-3-formic acid.

The yield was 65.1%. Example 4 80 mL of N,N-dimethylformamide dimethylacetal as both a sol- vent and a reaction raw material was taken to react with 2- aminopyridine (18.8 g, 200 mmol) at 60°C for 5 hours to obtain an N,N-dimethyl-N’-2-pyridinecarboxamidine intermediate after the re- action ended.

Rotary evaporation was carried out to remove exces- sive N,N-dimethylformamide dimethylacetal, 120 mL (125 g) of diox- ane, Na2c03{(15.9g, 150 mmol) and ethyl bromoacetate {50.1 g, 300 mmol) were added to react for 6 hours at 100°C.

After the reaction ended, the mixture was cooled to a room temperature, and 600 mL of water and 200 mL of ethyl acetate were added for extraction.

The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3*200 mL), the organic phases were combined, washed with water (2*150 mL), washed with 200 mL of a saturated saline solution, dried with anhydrous Na:S0,4, and filtered. The filtrate was concentrated to obtain a crude product of imid- azo[l,2-a] pyridine-3-ethyl formate, and the crude product was re- crystallized with a mixed solution of n-hexane and ethyl acetate in a ratio of 1: 1 (volume ratio) to obtain 26.1 g of pure prod- uct. The yield was 68.7%.

The imidazo[1,2-a] pyridine-3-ethyl formate (19.0 g, 100 mmol) and 100 mL of methanol were added to a 250 mL single-mouth flask. Sodium hydroxide (3.6 g, 150 mmol) was dissolved to 10 mL of water, added to a reaction flask, and stirred for 2 hours at 20°C. After the reaction ended, neutralization was carried out with 30% hydrochloric acid till the pH value was 5, suction filtration was carried out, and a filter cake was washed with a small amount of water, and was dried to obtain 11.2 g of a pure product of im- idazo[l,2-a] pyridine-3-formic acid. The yield was 69.0%.

Example 5 69 mL of N,N-dimethylformamide dimethylacetal as both a sol- vent and a reaction raw material was taken to react with 2- aminopyridine (18.8 g, 200 mmol) at 40°C for 8 hours to obtain an N,N-dimethyl-N’-2-pyridinecarboxamidine intermediate after the re- action ended. Rotary evaporation was carried out to remove exces- sive N,N-dimethylformamide dimethylacetal, 120 mL (62 g) of diox- ane, 60 mL (52 g) toluene, NaZC03(5.3 g, 50 mmol). K2C03(13.9 9, 100 mmol), KHCO3{(5 g, 50 mmol) and ethyl bromoacetate (33.4g, 200 mmol) were added to react for 15 hours at 60°C. After the reaction ended, the mixture was cooled to a room temperature, and 600 mL of water and 200 mL of ethyl acetate were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3*200 mL), the organic phases were combined, washed with water (2*150 mL), washed with 200 mL of a saturated saline solution, dried with anhydrous Na,S0,, and filtered. The filtrate was concentrated to obtain a crude product of imid- azo[1,2-a] pyridine-3-ethyl formate, and the crude product was re- crystallized with a mixed solution of n-hexane and ethyl acetate in a ratio of 1: 1 (volume ratio) to obtain 25.5 g of pure prod- uct. The yield was 67.1%.

The imidazo[1,2-a] pyridine-3-ethyl formate (19.0 g, 100 mmol) and 100 mL of methanol were added to a 250 mL single-mouth flask. Lithium hydroxide (1.2g, 50 mmol), sodium hydroxide (2g, 50 mmol) were dissolved to 10 mL of water, added to a reaction flask, and stirred for 1 hour at 80°C. After the reaction ended, neutrali- zation was carried out with 30% hydrochloric acid till the pH val- ue was 5, suction filtration was carried out, and a filter cake was washed with a small amount of water, and was dried to obtain

11.1 g of a pure product of imidazo[1,2-a] pyridine-3-formic acid. The yield was 68.4%. Example 6 97 mL of N,N-dimethylformamide dimethylacetal as both a sol- vent and a reaction raw material was taken to react with 2- aminopyridine (18.8 g, 200 mmol) at 100°C for 2 hours to obtain an N,N-dimethyl-N’-2-pyridinecarboxamidine intermediate after the re- action ended. Rotary evaporation was carried out to remove exces- sive N,N-dimethylformamide dimethylacetal, 20 mL (19 g) of N,N- dimethylformamide (DMF), 60 mL (é2g) of dioxane, 60 mL (52g) of toluene, Na2co3 (21.2g, 200 mmol), K2C03 (13.99, 100 mmol), KHCO3 ( 20 g, 200 mmol) and ethyl bromoacetate (83.59, 500 mmol) were added to react for 3 hours at 160°C. After the reaction ended, the mixture was cooled to a room temperature, and 600 mL of water and 200 mL of ethyl acetate were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3*200 mL), the organic phases were combined, washed with water (2*150 mL), washed with 200 mL of a saturated saline solution, dried with anhydrous Na,30;, and filtered. The filtrate was concentrated to obtain a crude product of imidazo[1,2-a] pyri- dine-3-ethyl formate, and the crude product was recrystallized with a mixed solution of n-hexane and ethyl acetate in a ratio of 1: 1 (volume ratio) to obtain 26.4 g of pure product. The yield was 69.4%. The imidazo[1,2-a] pyridine-3-ethyl formate (19.0 g, 100 mmol) and 140 mL of methanol were added to a 250 mL single-mouth flask. Lithium hydroxide (4.8 g, 200 mmol), sodium hydroxide (2g, 50 mmol) were dissolved to 20 mL of water, added to a reaction flask, and stirred for 5 hours at 20°C.

After the reaction ended, neutralization was carried out with 30% hydrochloric acid till the pH value was 5, suction filtration was carried out, and a filter cake was washed with a small amount of water, and was dried to ob- tain 11.3 g of a pure product of imidazo[1,2-a] pyridine-3-formic acid.

The yield was ©9.5%.

Claims (5)

CONCLUSIESCONCLUSIONS 1. Werkwijze voor het synthetiseren van imidazo[1,2-alpyridine-3- mierenzuur, welke werkwijze de volgende stappen omvat: (1) bereiding van imidazo[1,2-a]pyridine-3-ethylformiaat: N,N- dimethylformamidedimethylacetaal als zowel oplosmiddel als reac- tiegrondstof wordt in staat gesteld te reageren met 2- aminopyridine bij 40 - 100 °C gedurende 2 — 8 uur om een N,N- dimethyl-N'-2-pyridylformamidine als tussenproduct te verkrijgen, waardoor het tussenproduct, dat niet hoeft te worden gezuiverd, 3 - 15 uur kan reageren met ethylbroomacetaat bij 50 - 160 °C in een bepaald oplosmiddel onder de inwerking van een alkali, nadat de reactie is voltooid, afkoelen tot kamertemperatuur, extraheren met ethylacetaat, wassen met water en een zoutoplossing, drogen met watervrij natriumsulfaat, het uitvoeren van rotatieverdampingscon- centratie om een ruw product van imidazo[1,2-a]pyridine-3- ethylformiaat te verkrijgen, en het herkristalliseren van het ruwe product om een zuiver product te verkrijgen; en (2) bereiding van imidazo[1,2-a]pyridine-3-mierenzuur: onder in- werking van de alkali, een hydrolysereactie uitvoeren op het imi- dazo[1,;2-alpyridine-3-ethylformiaat voor 1 - 5 uur in een bepaald oplosmiddel, en nadat de reactie is afgelopen, neutraliseren met zoutzuur, filtreren, wassen met water en drogen om direct een zui- ver product van imidazo[1,2-a]pyridine-3-mierenzuur te verkrijgen.A method for synthesizing imidazo[1,2-alpyridine-3-formic acid, which method comprises the following steps: (1) preparation of imidazo[1,2-a]pyridine-3-ethylformate: N,N-dimethylformamide dimethylacetal as both solvent and reaction raw material is allowed to react with 2-aminopyridine at 40-100°C for 2-8 hours to obtain an intermediate N,N-dimethyl-N'-2-pyridylformamidine, thereby making the intermediate , which does not need to be purified, can react with ethyl bromoacetate at 50 - 160 °C for 3 - 15 hours in a certain solvent under the action of an alkali, after the reaction is completed, cool to room temperature, extract with ethyl acetate, wash with water and brine, drying with anhydrous sodium sulfate, conducting rotary evaporation concentration to obtain a crude product of imidazo[1,2-a]pyridine-3-ethylformate, and recrystallizing the crude product to obtain a pure product; and (2) preparation of imidazo[1,2-a]pyridine-3-formic acid: under the action of the alkali, perform a hydrolysis reaction on the imidazo[1,;2-a]pyridine-3-ethyl formate for 1- 5 hours in a certain solvent, and after the reaction is over, neutralize with hydrochloric acid, filter, wash with water and dry to directly obtain a pure product of imidazo[1,2-a]pyridine-3-formic acid. 2. Werkwijze voor het synthetiseren van imidazo[1,2-a]pyridine-3- mierenzuur volgens conclusie 1, waarbij in stap (1) een gemengde oplossing van n-hexaan en ethylacetaat in een volumeverhouding van 1:1 wordt aangenomen voor herkristallisatie.The method for synthesizing imidazo[1,2-a]pyridine-3-formic acid according to claim 1, wherein in step (1) a mixed solution of n-hexane and ethyl acetate in a volume ratio of 1:1 is adopted for recrystallization . 3. Werkwijze voor het synthetiseren van imidazo[1,2-a]pyridine-3- mierenzuur volgens conclusie 1, waarbij in stap (1) de molaire verhouding van N,N-dimethylformamide dimethylacetaal tot de 2- aminopyridine tot het alkali tot ethylbroomacetaat is (2,5-3,5) : 1: (1-2,5) : (1-2,5).The method for synthesizing imidazo[1,2-a]pyridine-3-formic acid according to claim 1, wherein in step (1), the molar ratio of N,N-dimethylformamide dimethylacetal to the 2-aminopyridine to the alkali to ethyl bromoacetate is (2.5-3.5) : 1 : (1-2.5) : (1-2.5). 4. Werkwijze voor het synthetiseren van imidazo[1,2-alpyridine-3- mierenzuur volgens conclusie 1, waarbij in stap (2) de alkali ten minste één van natriumhydroxide, kaliumhydroxide en lithiumhy- droxide is.The method for synthesizing imidazo[1,2-alpyridine-3-formic acid according to claim 1, wherein in step (2), the alkali is at least one of sodium hydroxide, potassium hydroxide and lithium hydroxide. 5. Werkwijze voor het synthetiseren van imidazo[1,2-a]pyridine-3- mierenzuur volgens conclusie 1, waarbij in stap (2) de hoeveelheid imidazo[1,2-a]pyridine-3-ethylformiaat tot de alkali 1 : (1-2,5) is.The method for synthesizing imidazo[1,2-a]pyridine-3-ethyl formate according to claim 1, wherein in step (2), the amount of imidazo[1,2-a]pyridine-3-ethyl formate to the alkali is 1: (1-2.5).