CN104829617A - Synthesis method for 6-fluoroimidazo[1, 2-a]pyridine-3-carbonitrile - Google Patents
Synthesis method for 6-fluoroimidazo[1, 2-a]pyridine-3-carbonitrile Download PDFInfo
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- 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 relates to a synthesis method for 6-fluoroimidazo[1, 2-a]pyridine-3-carbonitrile. The method includes: reacting N, N-dimethylformamide dimethylacetal with 2-amino-5-fluoropyridine at 40-100DEG C to obtain an N, N-dimethyl-N'-2-(5-fluoro-pyridine)yl-carboxamidine intermediate; without purification and under the action of alkali, subjecting the intermediate and bromoacetonitrile to reaction at 60-160DEG C in certain solvent, at the end of the reaction, adding water, then conducting extraction with ethyl acetate, performing washing with water and saturated salt solution, carrying out drying with anhydrous sodium sulfate, and conducting rotary evaporation concentration to obtain a 6-fluoroimidazo[1, 2-a]pyridine-3-carbonitrile crude product, recrystallizing the crude product to obtain a pure product. The reaction raw materials are easily available, the prices are reasonable, the reaction conditions are mild, the method is easy to operate and control, the aftertreatment is simple, and the product has stable quality and high purity.
Description
(1) technical field
The invention belongs to organic synthesis field, be specifically related to the synthetic method of a kind of 6-flumizole also [1,2-a] pyridine-3-formonitrile HCN.
(2) background technology
Disclose a kind of 4-[5-(pyridine-4-base)-1H-[1,2,4] three on April 16th, 2014
Azoles-3-base] preparation method of pyridine-2-formonitrile HCN.
Step one: formula (VI) compound iso methyl nicotinate and methane amide or carboxamide mixture are obtained by reacting formula (V) compound 2-methane amide iso methyl nicotinate in the environment of sulfuric acid, ferrous sulfate (i.e. iron vitriol) and hydrogen peroxide;
Step 2: formula (V) compound 2-methane amide iso methyl nicotinate obtains formula (IV) compound 2-cyano group iso methyl nicotinate through high-efficiency dehydration agent dehydration reaction;
Step 3: formula (IV) compound 2-cyano group iso methyl nicotinate and hydrazine hydrate are obtained by reacting formula (III) compound 2-cyano group vazadrine;
Step 4: formula (III) compound 2-cyano group vazadrine and formula (II) compound react to obtain formula (I) compound 4-[5-(pyridine-4-base)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN.4-[5-(pyridine-4-base)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN is 6-carbonitrile derivatives, 4-[5-(pyridin-4-yl)-1H-[1,2,4] triazole-3-base] pyridine-2-formonitrile HCN is a kind of non-purines xanthine oxidoreductase enzyme selectivity inhibitor, is used for the treatment of gout, hyperuricemia.In June, 2012, medicine Co., Ltd. of Fuji and three and chemistry institute jointly submit application for quotation to Japanese MHLW, on June 28th, 2013, Topiroxostat sheet gets the Green Light.
6-flumizole also [1,2-a] pyridine-3-formonitrile HCN, as a kind of 6-carbonitrile derivatives, is the important intermediate of organic synthesis, is mainly used in medicine intermediate, organic synthesis, organic solvent, also can be applicable to the aspects such as DYE PRODUCTION, pesticide producing and spices.This medicine intermediate is more novel, has very large using value.
(3) summary of the invention
The present invention needs the problem solved to be for prior art, and the invention provides the synthetic method of a kind of 6-flumizole also [1,2-a] pyridine-3-formonitrile HCN, this synthetic method is simple to operate, productive rate is high, is applicable to laboratory and suitability for industrialized production.
The present invention is achieved through the following technical solutions:
The synthetic method of a kind of 6-flumizole also [1,2-a] pyridine-3-formonitrile HCN, its special character is: comprise the following steps:
(1) N is prepared, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate: N, dinethylformamide dimethylacetal and 2-amino-5-fluorine pyridine react obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate at 40-100 DEG C;
(2) 6-flumizole also [1,2-a] pyridine-3-phenyl ketone: above-mentioned intermediate does not need to purify, under alkali effect, in certain solvent, react at 60-160 DEG C with bromoacetonitrile, reaction terminates, add water, then be extracted with ethyl acetate, water and saturated common salt water washing, anhydrous sodium sulfate drying, rotary evaporation concentrated after the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product recrystallization obtains sterling.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, temperature described in step (1) is 40 DEG C, 60 DEG C, 80 DEG C, 100 DEG C.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, reaction times 2-8 hour described in step (2).
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, the reaction times described in step (1) is 3 hours, 6 hours, 8 hours.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, described in step (2), solvent is dioxane, toluene, DMF, at least one in N,N-dimethylacetamide.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, described in step (2), alkali is saleratus, salt of wormwood, sodium bicarbonate, sodium carbonate, sodium hydroxide, at least one in potassium hydroxide.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, temperature described in step (2) is 60 DEG C, 100 DEG C, 120 DEG C, 160 DEG C.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, the reaction times described in step (2) is 3-15 hour.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, the reaction times described in step (2) is 8 hours, 10 hours, 12 hours, 15 hours.
The synthetic method of 6-flumizole of the present invention also [1,2-a] pyridine-3-formonitrile HCN, with the normal hexane of volume ratio 3:1 and ethyl acetate mixture recrystallization in step (2).
Its reaction is:
Beneficial effect of the present invention: reaction raw materials compares and is easy to get, reasonable price, reaction conditions is gentle, easy handling, is easy to control, and aftertreatment is simple, and constant product quality, purity is high.
(4) embodiment
Embodiment 1
80mL (71.7g, 600mmol) N, dinethylformamide dimethylacetal is solvent and reaction raw materials, reacts 3 hours with at 2-amino-5-fluorine pyridine (22.4g, 200mmol) 40 DEG C, reaction terminates obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation removes unnecessary DMF dimethylacetal, add 120 ml(125g) dioxane, NaHCO
3(25.2g, 300mmol) with bromoacetonitrile (35.99g, 300mmol), 100 DEG C are reacted 10 hours, reaction terminates, add 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merge organic phase, wash with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated 6-flumizole also [1,2-a] the thick product of pyridine-3-phenyl ketone, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 27.3g, productive rate 84.78%, fusing point: 173-176.5 DEG C.
Embodiment 2
80mL (71.7g, 600mmol) N, dinethylformamide dimethylacetal is solvent and reaction raw materials, reacts 6 hours with at 2-amino-5-fluorine pyridine (22.4g, 200mmol) 80 DEG C, reaction terminates obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation removes unnecessary DMF dimethylacetal, add 120 ml(125g) dioxane, NaHCO
3(25.2g, 300mmol) with bromoacetonitrile (28.79g, 240mmol), 120 DEG C are reacted 8 hours, reaction terminates, add 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merge organic phase, wash with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 27.9g, productive rate 86.65%, fusing point 173-176.5 DEG C.
Embodiment 3
80mL (71.7g, 600mmol) N, dinethylformamide dimethylacetal is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (22.4g, 200mmol) reaction 3 hours at 100 DEG C, reaction terminates obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation removes unnecessary N, dinethylformamide dimethylacetal, add 120 ml(125g) DMF, sodium hydroxide (12g, 300mmol) with bromoacetonitrile (35.99g, 300mmol), 160 DEG C are reacted 15 hours, reaction terminates, add 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merge organic phase, wash with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated 6-flumizole also [1,2-a] the thick product of pyridine-3-phenyl ketone, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 29.8g, productive rate 92.54%, fusing point: 173-176.5 DEG C.
Embodiment 4
67ml(60.08g, 500mmol) N, dinethylformamide dimethylacetal is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (22.4g, 200mmol) reaction 8 hours at 100 DEG C, reaction terminates obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation removes unnecessary N, dinethylformamide dimethylacetal, add 120 ml(125g) dioxane, potassium hydroxide (16.8g, 300mmol) with bromoacetonitrile (35.99g, 300mmol), 100 DEG C are reacted 12 hours, reaction terminates, add 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merge organic phase, wash with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated 6-flumizole also [1,2-a] the thick product of pyridine-3-phenyl ketone, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 23.6g, productive rate 73.29%, fusing point: 173-176.5 DEG C.
Embodiment 5
80mL (71.7g, 600mmol) N, dinethylformamide dimethylacetal is solvent and reaction raw materials, reacts 7 hours with at 2-amino-5-fluorine pyridine (22.4g, 200mmol) 60 DEG C, reaction terminates obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation removes unnecessary DMF dimethylacetal, add 120 ml toluene, KHCO
3(300mmol) with bromoacetonitrile (28.79g, 240mmol), 60 DEG C are reacted 15 hours, and reaction terminates, and adds 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merges organic phase, washes with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 27.8g, productive rate 86.6%, fusing point 173-176.5 DEG C.
Embodiment 6
80mL (71.7g, 600mmol) DMF dimethylacetal is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (22.4g, 200mmol) reaction 6 hours at 60 DEG C, reaction terminates obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, and rotary evaporation removes unnecessary N, dinethylformamide dimethylacetal, add 120 mlN, N-N,N-DIMETHYLACETAMIDE, K
2cO
3(300mmol) with bromoacetonitrile (28.79g, 240mmol), 90 DEG C are reacted 11 hours, and reaction terminates, and adds 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merges organic phase, washes with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 28.1g, fusing point 173-176.5 DEG C.
Embodiment 7
80mL (71.7g, 600mmol) DMF dimethylacetal is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (23.5g, 210mmol) reaction 6 hours at 70 DEG C, reaction terminates obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, and rotary evaporation removes unnecessary N, dinethylformamide dimethylacetal, add 120 mlN, N-N,N-DIMETHYLACETAMIDE, Na
2cO
3(300mmol) with bromoacetonitrile (28.79g, 240mmol), 90 DEG C are reacted 11 hours, and reaction terminates, and adds 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merges organic phase, washes with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 28.1g, fusing point 173-176.5 DEG C.
Embodiment 8
62mL N, dinethylformamide dimethylacetal is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (23.5g, 210mmol) reaction 0.5 hour at 102 DEG C, then 7 mlDMF are added, sodium hydroxide (0.7g) and bromoacetonitrile (4g) react reaction in 0.4 hour and terminate obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation removes unnecessary N, dinethylformamide dimethylacetal, add 200 mlN, N-N,N-DIMETHYLACETAMIDE, sodium hydroxide (300mmol) and bromoacetonitrile (28.79g, 240mmol), 155 DEG C are reacted 1 hour, reaction terminates, add 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merge organic phase, wash with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 28.5g, fusing point 173-176.5 DEG C.
Embodiment 9
62mL N, dinethylformamide dimethylacetal is solvent and reaction raw materials, with 2-amino-5-fluorine pyridine (23.5g, 210mmol) reaction 0.5 hour at 102 DEG C, then 7 ml dioxane are added, sodium hydroxide (0.7g) and bromoacetonitrile (4g) react reaction in 0.4 hour and terminate obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate, rotary evaporation removes unnecessary N, dinethylformamide dimethylacetal, add 200 ml dioxane, sodium hydroxide (300mmol) and bromoacetonitrile (28.79g, 240mmol), 101 DEG C are reacted 1 hour, reaction terminates, add 600 ml water and 200 ml extraction into ethyl acetate, separate organic phase, aqueous phase is extracted with ethyl acetate (3 × 200 ml), merge organic phase, wash with water (2 × 150 ml), 200 ml saturated common salt water washings, anhydrous Na
2sO
4drying, filters, after filtrate is concentrated the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product is through normal hexane: ethyl acetate=3:1(volume ratio) mixing solutions recrystallization obtain sterling 28.7g, fusing point 173-176.4 DEG C.
Claims (10)
1. the synthetic method of a 6-flumizole also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: comprise the following steps:
(1) N is prepared, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate: N, dinethylformamide dimethylacetal and 2-amino-5-fluorine pyridine react obtained N, N-dimethyl-N'-2-(the fluoro-pyridine of 5-) base-carbonamidine intermediate at 40-100 DEG C;
(2) 6-flumizole also [1,2-a] pyridine-3-phenyl ketone: above-mentioned intermediate does not need to purify, under alkali effect, in certain solvent, react at 60-160 DEG C with bromoacetonitrile, reaction terminates, add water, then be extracted with ethyl acetate, water and saturated common salt water washing, anhydrous sodium sulfate drying, rotary evaporation concentrated after the 6-flumizole also thick product of [1,2-a] pyridine-3-formonitrile HCN, this thick product recrystallization obtains sterling.
2. the synthetic method of 6-flumizole according to claim 1 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: temperature described in step (1) is 40 DEG C, 60 DEG C, 80 DEG C, 100 DEG C.
3. the synthetic method of 6-flumizole according to claim 1 and 2 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: reaction times 2-8 hour described in step (2).
4. the synthetic method of 6-flumizole according to claim 3 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: the reaction times described in step (1) is 3 hours, 6 hours, 8 hours.
5. the synthetic method of 6-flumizole according to claim 1 and 2 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: described in step (2), solvent is dioxane, toluene, DMF, at least one in N,N-dimethylacetamide.
6. the synthetic method of 6-flumizole according to claim 1 and 2 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: described in step (2), alkali is saleratus, salt of wormwood, sodium bicarbonate, sodium carbonate, sodium hydroxide, at least one in potassium hydroxide.
7. the synthetic method of 6-flumizole according to claim 1 and 2 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: temperature described in step (2) is 60 DEG C, 100 DEG C, 120 DEG C, 160 DEG C.
8. the synthetic method of 6-flumizole according to claim 1 and 2 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: the reaction times described in step (2) is 3-15 hour.
9. the synthetic method of 6-flumizole according to claim 8 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: the reaction times described in step (2) is 8 hours, 10 hours, 12 hours, 15 hours.
10. the synthetic method of 6-flumizole according to claim 1 and 2 also [1,2-a] pyridine-3-formonitrile HCN, is characterized in that: with the normal hexane of volume ratio 3:1 and ethyl acetate mixture recrystallization in step (2).
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933583A (en) * | 2010-06-15 | 2013-02-13 | 阿尔米雷尔有限公司 | Heteroaryl imidazolone derivatives as JAK inhibitors |
| CN103896941A (en) * | 2014-04-03 | 2014-07-02 | 定陶县友帮化工有限公司 | Synthesis method of 6-chloroimidazo[1,2-a]pyridine-3-formonitrile |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933583A (en) * | 2010-06-15 | 2013-02-13 | 阿尔米雷尔有限公司 | Heteroaryl imidazolone derivatives as JAK inhibitors |
| CN103896941A (en) * | 2014-04-03 | 2014-07-02 | 定陶县友帮化工有限公司 | Synthesis method of 6-chloroimidazo[1,2-a]pyridine-3-formonitrile |
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