CN104744463A - Method for synthesizing 6-chloro-8-bromoimidazo[1,2-a]pyridine - Google Patents
Method for synthesizing 6-chloro-8-bromoimidazo[1,2-a]pyridine Download PDFInfo
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- CN104744463A CN104744463A CN201510146393.1A CN201510146393A CN104744463A CN 104744463 A CN104744463 A CN 104744463A CN 201510146393 A CN201510146393 A CN 201510146393A CN 104744463 A CN104744463 A CN 104744463A
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- chloropyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to a method for synthesizing 6-chloro-8-bromoimidazo[1,2-a]pyridine. The method comprises the following steps: enabling 2-amino-5-chloropyridine and N-bromo succinimide to react at the temperature of 0-100 DEG C so as to prepare a 2-amino-3-bromo-5-chloropyridine intermediate, and enabling the intermediate to react with chloroacetaldehyde at the temperature of 70-160 DEG C in a certain solvent without being purified; after reaction ends, carrying out suction filtration, dissolving in a certain solvent, neutralizing in the presence of alkali, carrying out suction filtration, re-crystallizing, carrying out suction filtration, washing with water, and drying, thereby directly obtaining pure 6-chloro-8-bromoimidazopyridine. According to the method, the raw materials are relatively easily obtained and are reasonable in price; meanwhile, during preparation reaction, no heavy metal and corrosive gas are used, the reaction is mild, no special requirements on reaction equipment are required, and ordinary corrosion-resistant equipment can be applied to production; in addition, reaction conditions of the method are moderate.
Description
(1) technical field
The invention belongs to organic synthesis field, be specifically related to the synthetic method of a kind of 6-chloro-8-bromine imidazo [1,2-a] pyridine.
(2) background technology
6-chloro-8-bromine imidazo [1,2-a] pyridine 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 product is novel medicine intermediate, and have very large medical value, it synthesizes difficulty, and market value is expensive, lacks document and Patents report.
(3) summary of the invention
The present invention needs the problem solved to be for prior art, and provide a kind of technique advantages of simple, cost low, product purity is high, is suitable for the synthetic method of industrialized 6-chloro-8-bromine imidazo [1,2-a] pyridine.
The present invention is achieved through the following technical solutions:
The synthetic method of a kind of 6-chloro-8-bromine imidazo [1,2-a] pyridine, its special character is: comprise the following steps:
(1) 2-amino-5-chloropyridine and N-bromo-succinimide react at 0-100 DEG C, obtained 2-amino-3-bromo-5-chloropyridine intermediate, and this intermediate does not need to purify, and in certain solvent, to react terminate with monochloroacetaldehyde at 70-160 DEG C;
(2) suction filtration after reaction knot, dissolves in certain solvent, under the effect of alkali and, suction filtration, recrystallization, suction filtration, washing, dries direct 6-chloro-8-bromine imidazo [1,2-a] pyridine sterling.
6-of the present invention chloro-8-bromine imidazo [1,2-a] synthetic method of pyridine, described in step (1), 2-amino-5-chloropyridine and N-bromo-succinimide are raw material, and the ratio of amount of substance is 1:0.5-5,2-amino-5-chloropyridine is 1:0.5-5 with the ratio of monochloroacetaldehyde amount of substance.
The synthetic method of 6-of the present invention chloro-8-bromine imidazo [1,2-a] pyridine, the charging capacity of the reactant described in step (1) and solvent is: m2-amino-5-chloropyridine: m solvent=1:1-5.5, is the ratio of weight.
The synthetic method of 6-of the present invention chloro-8-bromine imidazo [1,2-a] pyridine, described in step (1), solvent is acetonitrile, dioxane, toluene, DMF, at least one in N,N-dimethylacetamide.
The synthetic method of 6-of the present invention chloro-8-bromine imidazo [1,2-a] pyridine, described in step (2), solvent is acetonitrile, ethanol, ethanol and water mixture, DMF, at least one in N,N-dimethylacetamide.
The synthetic method of 6-of the present invention chloro-8-bromine imidazo [1,2-a] pyridine, with the normal hexane of volume ratio 3:1 and ethyl acetate mixture recrystallization in step (2).
The synthetic method of 6-of the present invention chloro-8-bromine imidazo [1,2-a] pyridine, in step (2), alkali is at least one in sodium hydroxide, potassium hydroxide and lithium hydroxide.
Synthesis technique and the synthesis step of 6-of the present invention chloro-8-bromine imidazo [1,2-a] pyridine are as follows:
Beneficial effect of the present invention: raw material ratio of the present invention is comparatively easy to get, reasonable price, simultaneously do not use heavy metal and corrosive gases in preparation feedback, reaction temperature and, special requirement is not had to reflection equipment, common corrosion resistant apparatus can be produced, reaction conditions of the present invention is moderate in addition, and reaction is easy to control, and aftertreatment is simple, product purity etc. superiority condition, this technique is easy to promote.
(4) embodiment
Embodiment 1:
In the round bottom single port flask of a 100ml, add N,N-dimethylacetamide 12.85g, insert thermometer and start magnetic stirring apparatus, and add the 2-amino-5-chloropyridine of 12.85g, add 8.9gN-bromo-succinimide, react and react 6 hours at 15 DEG C, TLC and GC determines that reaction completes.Do not need to purify, add the aqueous chloroacetaldehyde solution 9.8g of 40%, reaction 10 hours under stirring at 70 DEG C.TLC and GC determines that reaction completes.Reaction knot after suction filtration, dissolve in acetonitrile, under the effect of potassium hydroxide and, suction filtration, with normal hexane and the ethyl acetate mixture recrystallization of volume ratio 3:1, suction filtration, washing, dry direct obtain 6-chloro-8-bromine imidazo [1,2-a] pyridine sterling.Sterling 9.26g is obtained, productive rate 40% after drying.Nuclear magnetic resonance spectroscopy, 1H NMR (CD3Cl) 300 MHz: δ 8.185 ppm (d, J=1.2Hz, 1H); 7.716 ppm (d, J=0.9Hz, 1H): 7.652 ppm (d, J=0.9Hz): 7.459 ppm (d, J=1.2Hz, 1H).
Embodiment 2:
Acetonitrile 12.85g is added in the round bottom single port flask of a 100ml, insert thermometer and start magnetic stirring apparatus, and add the 2-amino-5-chloropyridine of 12.85g, add 8.9gN-bromo-succinimide, reaction is reacted 7 hours at 15 DEG C, TLC and GC determines that reaction completes.Do not need to purify, add the aqueous chloroacetaldehyde solution 9.8g of 40%, reaction 10 hours under stirring at 70 DEG C.TLC and GC determines that reaction completes.Reaction knot after suction filtration, dissolve in ethanol, under the effect of potassium hydroxide and, suction filtration, with normal hexane and the ethyl acetate mixture recrystallization of volume ratio 3:1, suction filtration, washing, dry direct obtain 6-chloro-8-bromine imidazo [1,2-a] pyridine sterling.Sterling 11.57g is obtained, productive rate 50% after drying.Nuclear magnetic resonance spectroscopy, 1H NMR (CD3Cl) 300 MHz: δ 8.185 ppm (d, J=1.2Hz, 1H); 7.716 ppm (d, J=0.9Hz, 1H): 7.652 ppm (d, J=0.9Hz): 7.459 ppm (d, J=1.2Hz, 1H).
Embodiment 3:
In the round bottom single port flask of a 100ml, add DMF 12.85g, insert thermometer and start magnetic stirring apparatus, and add the 2-amino-5-chloropyridine of 12.85g, add 35.6gN-bromo-succinimide, react and react 6 hours at 15 DEG C, TLC and GC determines that reaction completes.Do not need to purify, add the aqueous chloroacetaldehyde solution 9.8g of 40%, reaction 9 hours under stirring at 70 DEG C.TLC and GC determines that reaction completes.Reaction knot after suction filtration, dissolve in ethanol, under the effect of lithium hydroxide and, suction filtration, with normal hexane and the ethyl acetate mixture recrystallization of volume ratio 3:1, suction filtration, washing, dry direct obtain 6-chloro-8-bromine imidazo [1,2-a] pyridine sterling.Sterling 13.89g is obtained, productive rate 60% after drying.Nuclear magnetic resonance spectroscopy, 1H NMR (CD3Cl) 300 MHz: δ 8.185 ppm (d, J=1.2Hz, 1H); 7.716 ppm (d, J=0.9Hz, 1H): 7.652 ppm (d, J=0.9Hz): 7.459 ppm (d, J=1.2Hz, 1H).
Embodiment 4:
In the round bottom single port flask of a 100ml, add DMF 12.85g, insert thermometer and start magnetic stirring apparatus, and add the 2-amino-5-chloropyridine of 12.85g, add 35.6gN-bromo-succinimide, react and react 6 hours at 15 DEG C, TLC and GC determines that reaction completes.Do not need to purify, add the aqueous chloroacetaldehyde solution 19.62g of 40%, reaction 9 hours under stirring at 70 DEG C.TLC and GC determines that reaction completes.Reaction knot after suction filtration, dissolve in ethanol, under the effect of sodium hydroxide and, suction filtration, with normal hexane and the ethyl acetate mixture recrystallization of volume ratio 3:1, suction filtration, washing, dry direct obtain 6-chloro-8-bromine imidazo [1,2-a] pyridine sterling.Sterling 16.21g is obtained, productive rate 70% after drying.Nuclear magnetic resonance spectroscopy, 1H NMR (CD3Cl) 300 MHz: δ 8.185 ppm (d, J=1.2Hz, 1H); 7.716 ppm (d, J=0.9Hz, 1H): 7.652 ppm (d, J=0.9Hz): 7.459 ppm (d, J=1.2Hz, 1H).
Embodiment 5:
In the round bottom single port flask of a 100ml, add dioxane 10g, toluene 10g, insert thermometer and start magnetic stirring apparatus, and add the 2-amino-5-chloropyridine of 12.85g, add 35.6gN-bromo-succinimide, react and react 0.4 hour at 95 DEG C, TLC and GC determines that reaction completes.Do not need to purify, add the aqueous chloroacetaldehyde solution 17g of 35%, reaction 0.5 hour under stirring at 105 DEG C.TLC and GC determines that reaction completes.Reaction knot after suction filtration, dissolve in DMF, under the effect of potassium hydroxide and, suction filtration, with normal hexane and the ethyl acetate mixture recrystallization of volume ratio 3:1, suction filtration, washing, dries direct 6-chloro-8-bromine imidazo [1,2-a] pyridine sterling.Sterling 19.22g is obtained, productive rate 83% after drying.
Claims (7)
1. the synthetic method of 6-chloro-8-bromine imidazo [1, a 2-a] pyridine, is characterized in that: comprise the following steps:
(1) 2-amino-5-chloropyridine and N-bromo-succinimide react at 0-100 DEG C, obtained 2-amino-3-bromo-5-chloropyridine intermediate, and this intermediate does not need to purify, and in certain solvent, to react terminate with monochloroacetaldehyde at 70-160 DEG C;
(2) suction filtration after reaction knot, dissolves in certain solvent, under the effect of alkali and, suction filtration, recrystallization, suction filtration, washing, dries direct 6-chloro-8-bromine imidazo [1,2-a] pyridine sterling.
2. 6-according to claim 1 chloro-8-bromine imidazo [1,2-a] synthetic method of pyridine, it is characterized in that: described in step (1), 2-amino-5-chloropyridine and N-bromo-succinimide are raw material, the ratio of amount of substance is 1:0.5-5,2-amino-5-chloropyridine is 1:0.5-5 with the ratio of monochloroacetaldehyde amount of substance.
3. the synthetic method of 6-according to claim 1 chloro-8-bromine imidazo [1,2-a] pyridine, is characterized in that: the charging capacity of the reactant described in step (1) and solvent is: m
2-amino-5-chloropyridine: m
solvent=1:1-5.5 is the ratio of weight.
4. the synthetic method of 6-according to claim 1 chloro-8-bromine imidazo [1,2-a] pyridine, is characterized in that: described in step (1), solvent is acetonitrile, dioxane, toluene, DMF, at least one in N,N-dimethylacetamide.
5. the synthetic method of 6-according to claim 1 chloro-8-bromine imidazo [1,2-a] pyridine, is characterized in that: described in step (2), solvent is acetonitrile, ethanol, ethanol and water mixture, N, dinethylformamide, at least one in N,N-dimethylacetamide.
6. the synthetic method of 6-according to claim 1 chloro-8-bromine imidazo [1,2-a] pyridine, is characterized in that: with the normal hexane of volume ratio 3:1 and ethyl acetate mixture recrystallization in step (2).
7. the synthetic method of 6-according to claim 1 chloro-8-bromine imidazo [1,2-a] pyridine, is characterized in that: in step (2), alkali is at least one in sodium hydroxide, potassium hydroxide and lithium hydroxide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104016909A (en) * | 2014-04-03 | 2014-09-03 | 定陶县友帮化工有限公司 | Synthetic method of 2-amino-3-bromo-5-chloropyridine |
| CN104105697A (en) * | 2011-11-03 | 2014-10-15 | 霍夫曼-拉罗奇有限公司 | Bicyclic piperazine compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104105697A (en) * | 2011-11-03 | 2014-10-15 | 霍夫曼-拉罗奇有限公司 | Bicyclic piperazine compounds |
| CN104016909A (en) * | 2014-04-03 | 2014-09-03 | 定陶县友帮化工有限公司 | Synthetic method of 2-amino-3-bromo-5-chloropyridine |
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Application publication date: 20150701 |