CN103864786A - Method for synthesizing 6-fluoroimidazo-[1,2-a]-pyridine-3-formic acid - Google Patents
Method for synthesizing 6-fluoroimidazo-[1,2-a]-pyridine-3-formic acid Download PDFInfo
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- CN103864786A CN103864786A CN201410091740.0A CN201410091740A CN103864786A CN 103864786 A CN103864786 A CN 103864786A CN 201410091740 A CN201410091740 A CN 201410091740A CN 103864786 A CN103864786 A CN 103864786A
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- flumizole
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the field of organic synthesis and in particular relates to a method for synthesizing 6-fluoroimidazo-[1,2-a]-pyridine-3-formic acid. The method comprises the following steps: reacting 2-amino-5-fluoropyridine and N,N-dimethylformamide dimethylacetal as raw materials at 40-100 DEG C for 2-8 hours to obtain N,N-dimethyl-N'-2-(5-fluoro-pyridine)-yl-formamidine intermediate which does not need to be purified, reacting with ethyl bromoacetate in a solvent a in the presence of alkali at 100-160 DEG C for 2-8 hours to generate 6-fluoroimidazo-[1,2-a]-pyridine-3-ethyl formate, and hydrolyzing 6-fluoroimidazo-[1,2-a]-pyridine-3-ethyl formate in a solvent b through alkali at certain temperature to obtain 6-fluoroimidazo-[1,2-a]-pyridine-3-formic acid. The method has the beneficial effects that the raw materials are easily available and reasonable in price, heavy metal and corrosive gas are not used, the reaction is mild, general corrosion-resistant equipment can be used for production, the reaction conditions are moderate, the reaction process is easy to control, the post-treatment operation is easy, the product purity is high, and the popularization is facilitated.
Description
Technical field
The invention belongs to organic synthesis field, particularly the also synthetic method of [1,2-a] Nicotinicum Acidum of a kind of 6-flumizole.
Background technology
6-flumizole also [1,2-a] Nicotinicum Acidum is a kind of new, important organic synthesis intermediate, and particularly, in pharmaceutical chemical research and application, its more function group or potential more function group are its key points that is used to organic synthesis.Therefore, develop a kind of raw material cheap and easy to get, easy and simple to handle, reaction conditions gentleness, production cost is low, and productive rate is high, is applicable to scale operation, and the method for storage, production process safety is completely necessary.
Summary of the invention
The present invention, in order to make up the defect of prior art, provides a kind of and can be applied to laboratory and the synthetic also synthetic method of [1,2-a] Nicotinicum Acidum of 6-flumizole of industrialization.
The present invention is achieved through the following technical solutions:
The also synthetic method of [1,2-a] Nicotinicum Acidum of a kind of 6-flumizole, is characterized in that, comprises the following steps:
(1) with 2-amino-5-fluorine pyridine and N, dinethylformamide dimethylacetal is raw material, within 2 ~ 8 hours, make N 40 ~ 100 ℃ of reactions, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, this intermediate does not need to purify, under alkali a effect, in solvent a, react and within 2 ~ 8 hours, generate 6-flumizole also [1 at 100 ~ 160 ℃ with ethyl bromoacetate, 2-a] pyridone-3-carboxylic acid ethyl ester, extract through ethyl acetate, water washing, anhydrous sodium sulfate drying, after rotary evaporation is concentrated 6-flumizole also [1, 2-a] the thick product of pyridone-3-carboxylic acid ethyl ester, obtain sterling through recrystallization,
(2) under alkali b effect, 6-flumizole also [1,2-a] pyridone-3-carboxylic acid ethyl ester in solvent b in 10 ~ 90 ℃ of hydrolysis reaction 1 ~ 5 hour, through hydrochloric acid neutralization, filter, wash, dry direct also [1,2-a] pyridone-3-carboxylic acid sterling of 6-flumizole.
In described step (1), reactant charging capacity is: 2-amino-5-fluorine pyridine: DMF dimethylacetal=1:3 is more than mol ratio.
In described step (1), solvent a is dioxane, toluene, DMF (DMF), DMF and one in methylal.
In described step (1), alkali a is saleratus, salt of wormwood, sodium bicarbonate, the one in sodium carbonate.
In described step (1), recrystallization solution is normal hexane and ethyl acetate mixture, and normal hexane: ethyl acetate=6:1 is more than volume ratio.
In described step (2), more excellent temperature of reaction is 20 ℃, 40 ℃, 60 ℃ and 80 ℃.
In described step (2), solvent b refers to the one in methyl alcohol, second alcohol and water.
In described step (2), alkali b refers to the one in sodium hydroxide, potassium hydroxide and lithium hydroxide.
The invention has the beneficial effects as follows: raw material of the present invention is easy to get, reasonable price, does not use heavy metal and corrosive gases, reaction temperature and, common corrosion resistant apparatus can be produced, and reaction conditions of the present invention is moderate in addition, and reaction is easy to control, aftertreatment is simple, and product purity is high, is easy to promote.
Embodiment
Embodiment 1:
N, dinethylformamide dimethylacetal (80 mL) is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (22.4g, 200mmol) reflux stirring reaction 3 hours, reaction finished to make N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation is removed unnecessary DMF dimethylacetal, adds 150 mL N, dinethylformamide (DMF), NaHCO
3(25.2g, 300mmol) and ethyl bromoacetate (50.1g, 300 mmol), reflux 10 hours, reaction finishes, and is chilled to room temperature, adds 600 mL water and the extraction of 200 mL ethyl acetate, separate organic phase, water is extracted with ethyl acetate (3 × 200 mL), merges organic phase, washes (2 × 150 mL) with water, 200 mL saturated common salt water washings, anhydrous Na
2sO
4dry, filter, filtrate rotary evaporation obtains the also thick product of [1,2-a] pyridone-3-carboxylic acid ethyl ester of 6-flumizole after removing volume, this thick product is through normal hexane: ethyl acetate=6:1(volume ratio) mixing solutions recrystallization obtain sterling 28.6g, productive rate 68.7%, fusing point: 51.5-53.5 ℃, 1HNMR (400Hz, CDCl3) δ: 9.27 (s, 1H), 8.30 (s, 1H), 7.71 (d, 1H), 7.34 (d, 1H), 4.41 (m, 2H), 1.42 (t, 3H).
In 250mL single port flask, add 6-flumizole also in [1,2-a] pyridone-3-carboxylic acid ethyl ester (20.8g, 100mmol) and 100mL methyl alcohol, sodium hydroxide (6.0g, 150mmol) is dissolved in 10mL water, joins in reaction flask, under room temperature, stir 2 h, reaction finishes, and is neutralized to PH=4, suction filtration with 30% hydrochloric acid, the a small amount of water washing of filter cake, after dry, obtain also [1,2-a] pyridone-3-carboxylic acid sterling 14.7g of 6-flumizole, productive rate 81.6%.Fusing point 250.2-251.6 ℃, 1HNMR (400Hz, DMSO-d6) δ: 11.0 (s, 1H), 9.30 (s, 1H), 8.53 (s, 1H), 7.78 (d, 1H), 7.45 (d, 1H).
Embodiment 2:
N, dinethylformamide dimethylacetal (80 mL) is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (22.4g, 200mmol) reflux stirring reaction 3 hours, reaction finished to make N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation is removed unnecessary DMF dimethylacetal, adds 150 mL N, dinethylformamide (DMF), K
2cO
3(20.8g, 150mmol) and ethyl bromoacetate (50.1g, 300mmol), reflux 10 hours, reaction finishes, and is chilled to room temperature, adds 600 mL water and the extraction of 200 mL ethyl acetate, separate organic phase, water is extracted with ethyl acetate (3 × 200 mL), merges organic phase, washes (2 × 150 mL) with water, 200 mL saturated common salt water washings, anhydrous Na
2sO
4dry, filter, filtrate rotary evaporation is removed after volume to obtain the also thick product of [1,2-a] pyridone-3-carboxylic acid ethyl ester of 6-flumizole, this thick product is through normal hexane: ethyl acetate=6:1(volume ratio) mixing solutions recrystallization obtain sterling 25.9g, productive rate 62.3%.
In 250mL single port flask, add 6-flumizole also in [1,2-a] pyridone-3-carboxylic acid ethyl ester (20.8g, 100mmol) and 100mL methyl alcohol, potassium hydroxide (8.4g, 150mmol) is dissolved in 10mL water, joins in reaction flask, under room temperature, stir 2 h, reaction finishes, and is neutralized to PH=5 with 30% hydrochloric acid, suction filtration, the a small amount of water washing of filter cake, obtains also [1,2-a] pyridone-3-carboxylic acid sterling of 6-flumizole after being dried, 15.3g, productive rate 85.1%.
Embodiment 3:
N, dinethylformamide dimethylacetal (80 mL) is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (22.4g, 200mmol) reflux stirring reaction 3 hours, reaction finishes to make N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation is removed unnecessary N, dinethylformamide dimethylacetal, add 150 mL N, dinethylformamide (DMF), add triethylamine (30.3g, 300mmol) and ethyl bromoacetate (50.1g, 300mmol), reflux 10 hours, reaction finishes, be chilled to room temperature, add 600 mL water and the extraction of 200 mL ethyl acetate, separate organic phase, water is extracted with ethyl acetate (3 × 200 mL), merge organic phase, wash (2 × 150 mL) with water, 200 mL saturated common salt water washings, anhydrous Na
2sO
4dry, filter, filtrate rotary evaporation is removed after volume to obtain the also thick product of [1,2-a] pyridone-3-carboxylic acid ethyl ester of 6-flumizole, this thick product is through normal hexane: ethyl acetate=6:1(volume ratio) mixing solutions recrystallization obtain sterling 24.6g, productive rate 59.1%.
In 250mL single port flask, add 6-flumizole also in [1,2-a] pyridone-3-carboxylic acid ethyl ester (20.8g, 100mmol) and 100mL methyl alcohol, sodium hydroxide (6.0g, 150mmol) is dissolved in 10mL water, joins in reaction flask, under room temperature, stir 2 h, reaction finishes, and is neutralized to PH=4, suction filtration with 30% hydrochloric acid, the a small amount of water washing of filter cake, also [1,2-a] pyridone-3-carboxylic acid sterling 14.4g of 6-flumizole, productive rate 80.1% after dry, were both obtained.
Embodiment 4:
N, dinethylformamide dimethylacetal (80 mL) is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (22.4g, 200mmol) reflux stirring reaction 3 hours, reaction finished to make N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation is removed unnecessary DMF dimethylacetal, adds 150 mL N, dinethylformamide (DMF), Na
2cO
3(15.9g, 150mmol) and ethyl bromoacetate (50.1g, 300mmol), reflux 10 hours, reaction finishes, and reaction finishes, be chilled to room temperature, add 600 mL water and the extraction of 200 mL ethyl acetate, separate organic phase, water is extracted with ethyl acetate (3 × 200 mL), merge organic phase, wash (2 × 150 mL) with water, 200 mL saturated common salt water washings, anhydrous Na
2sO
4dry, filter, filtrate rotary evaporation is removed after volume to obtain the also thick product of [1,2-a] pyridone-3-carboxylic acid ethyl ester of 6-flumizole, this thick product is through normal hexane: ethyl acetate=6:1(volume ratio) mixing solutions recrystallization obtain sterling 21.2g, productive rate 50.8%.
In 250mL single port flask, add 6-flumizole also in [1,2-a] pyridone-3-carboxylic acid ethyl ester (20.8g, 100mmol) and 100mL methyl alcohol, lithium hydroxide (3.6g, 150mmol) is dissolved in 10mL water, joins in reaction flask, under room temperature, stir 2 h, reaction finishes, and is neutralized to PH=5, suction filtration with 30% hydrochloric acid, the a small amount of water washing of filter cake, also [1,2-a] pyridone-3-carboxylic acid sterling 16.0g of 6-flumizole, productive rate 89.0% after dry, were both obtained.
Claims (8)
1. the also synthetic method of [1,2-a] Nicotinicum Acidum of a 6-flumizole, is characterized in that, comprises the following steps:
(1) with 2-amino-5-fluorine pyridine and N, dinethylformamide dimethylacetal is raw material, within 2 ~ 8 hours, make N 40 ~ 100 ℃ of reactions, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, this intermediate does not need to purify, under alkali a effect, in solvent a, react and within 2 ~ 8 hours, generate 6-flumizole also [1 at 100 ~ 160 ℃ with ethyl bromoacetate, 2-a] pyridone-3-carboxylic acid ethyl ester, extract through ethyl acetate, water washing, anhydrous sodium sulfate drying, after rotary evaporation is concentrated 6-flumizole also [1, 2-a] the thick product of pyridone-3-carboxylic acid ethyl ester, obtain sterling through recrystallization,
(2) under alkali b effect, 6-flumizole also [1,2-a] pyridone-3-carboxylic acid ethyl ester in solvent b in 10 ~ 90 ℃ of hydrolysis reaction 1 ~ 5 hour, through hydrochloric acid neutralization, filter, wash, dry direct also [1,2-a] pyridone-3-carboxylic acid sterling of 6-flumizole.
2. 6-flumizole according to claim 1 also [1,2-a] synthetic method of Nicotinicum Acidum, it is characterized in that: in described step (1), reactant charging capacity is: 2-amino-5-fluorine pyridine: N, dinethylformamide dimethylacetal=1:3 is more than mol ratio.
3. the also synthetic method of [1,2-a] Nicotinicum Acidum of 6-flumizole according to claim 1, is characterized in that: in described step (1), solvent a is dioxane, toluene, N, dinethylformamide (DMF), DMF and one in methylal.
4. the also synthetic method of [1,2-a] Nicotinicum Acidum of 6-flumizole according to claim 1, is characterized in that: in described step (1), alkali a is saleratus, salt of wormwood, sodium bicarbonate, the one in sodium carbonate.
5. 6-flumizole according to claim 1 also [1,2-a] synthetic method of Nicotinicum Acidum, it is characterized in that: in described step (1), recrystallization solution is normal hexane and ethyl acetate mixture, normal hexane: ethyl acetate=6:1 is more than volume ratio.
6. the also synthetic method of [1,2-a] Nicotinicum Acidum of 6-flumizole according to claim 1, is characterized in that: in described step (2), more excellent temperature of reaction is 20 ℃, 40 ℃, 60 ℃ and 80 ℃.
7. the also synthetic method of [1,2-a] Nicotinicum Acidum of 6-flumizole according to claim 1, is characterized in that: in described step (2), solvent b refers to the one in methyl alcohol, second alcohol and water.
8. the also synthetic method of [1,2-a] Nicotinicum Acidum of 6-flumizole according to claim 1, is characterized in that: in described step (2), alkali b refers to the one in sodium hydroxide, potassium hydroxide and lithium hydroxide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829615A (en) * | 2015-04-25 | 2015-08-12 | 山东友帮生化科技有限公司 | Synthesis method for 6-fluoroimidazo[1, 2-a]pyridine-3-phenyl ketone |
| CN110590771A (en) * | 2019-09-05 | 2019-12-20 | 南通大学 | [1,5-a ] -pyridylimidazole-1-nitrile and chemical synthesis method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012034091A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors |
| CN103130792A (en) * | 2011-11-30 | 2013-06-05 | 江苏正大天晴药业股份有限公司 | 2-aminothiazoles compound |
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2014
- 2014-03-13 CN CN201410091740.0A patent/CN103864786A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012034091A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors |
| CN103130792A (en) * | 2011-11-30 | 2013-06-05 | 江苏正大天晴药业股份有限公司 | 2-aminothiazoles compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829615A (en) * | 2015-04-25 | 2015-08-12 | 山东友帮生化科技有限公司 | Synthesis method for 6-fluoroimidazo[1, 2-a]pyridine-3-phenyl ketone |
| CN110590771A (en) * | 2019-09-05 | 2019-12-20 | 南通大学 | [1,5-a ] -pyridylimidazole-1-nitrile and chemical synthesis method thereof |
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