CN106957259A - A kind of synthetic method of 3,5- dibromo pyridines - Google Patents
A kind of synthetic method of 3,5- dibromo pyridines Download PDFInfo
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- CN106957259A CN106957259A CN201610014465.1A CN201610014465A CN106957259A CN 106957259 A CN106957259 A CN 106957259A CN 201610014465 A CN201610014465 A CN 201610014465A CN 106957259 A CN106957259 A CN 106957259A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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Abstract
The invention discloses the synthetic method of one kind 3,5- dibromo pyridines, including：（1）Bromination reaction：4-aminopyridine and azodiisobutyronitrile are dissolved in carbon tetrachloride, control monitoring in N- bromo-succinimides, liquid phase is added at 25 DEG C and, to reacting complete, handles to obtain the bromo- 4-aminopyridines of 3,5- bis-；（2）Diazo-reaction：The bromo- 4-aminopyridines of 3,5- bis- are added in the concentrated sulfuric acid, until completely dissolved, nitrosylsulfuric acid are added dropwise at 48~55 DEG C, 1~1.5h is reacted after stopping being added dropwise when potassium iodide starch test paper becomes blue and does not take off；（3）Reduction reaction：Continue to add after nickel powder and ethanol solution into above-mentioned solution, back flow reaction is adjusted to alkalescent after cooling with strong caustic, produces through processing.Reaction condition of the present invention is gentle, high income, and raw material is easy to get, and cost is relatively low, and process route is short, and product purity is high, with industrial prospect.
Description
Technical field
It is specifically the synthetic method of one kind 3,5- dibromo pyridines the present invention relates to medicine intermediate synthesis technical field.
Background technology
Pyridine and its derivatives are widely distributed in nature.All contain pyridine cycle compound in the structure of many plant components such as alkaloid, they are the bases for producing many important compounds, are indispensable raw materials in the production such as medicine, agricultural chemicals, dyestuff, surfactant, rubber chemicals, feed addictive, food additives, adhesive.
3,5- dibromo pyridines are important medicine intermediates, are the important source materials for synthesizing prevention and treatment CNS disorders TC-2559.Because the fragrant electrophilic reaction speed of pyridine generation is more more slowly than benzene, it is often necessary to violent reaction condition, and only 3- substitution reaction product generation.The synthetic method of existing 3,5- dibromo pyridines not only severe reaction conditions, and have single bromo accessory substance, cause low yield, and separation is difficult.
The content of the invention
It is an object of the invention to provide a kind of reaction condition is gentle, the 3,5- dibromo pyridines of high income synthetic method.
To achieve the above object, the present invention provides following technical scheme：
The synthetic method of one kind 3,5- dibromo pyridines, comprises the following steps：
（1）Bromination reaction：4-aminopyridine is added in there-necked flask and azodiisobutyronitrile is dissolved in carbon tetrachloride, N- bromo-succinimides are added at 25 DEG C, is reacted control monitoring in 18~22h, liquid phase and, to reacting complete, is stopped reaction；Reaction solution is stirred down and is cooled to after room temperature, pour into carbon tetrachloride and stir, filter, filter cake is washed twice with carbon tetrachloride, filtrate washed once with sodium bicarbonate aqueous solution, and saturated aqueous common salt washed once, and revolving eliminates carbon tetrachloride, recrystallized again with petroleum ether, obtain white solid, the bromo- 4-aminopyridines of as 3,5- bis-；
（2）Diazo-reaction：The concentrated sulfuric acid and 3 that concentration is 16.90~17.8mol/L is added in there-necked flask, the bromo- 4-aminopyridines of 5- bis-, treat 3, after the bromo- 4-aminopyridines of 5- bis- are completely dissolved, nitrosylsulfuric acid is added dropwise at 48~55 DEG C, reaction end is examined using potassium iodide starch test paper, 1~1.5h is reacted after stopping being added dropwise when reaction solution makes potassium iodide starch test paper become blue and not take off, obtain the bromo- 4- pyridine-sulfonic acids of 3,5- bis-；
（3）Reduction reaction：Contain 3 toward above-mentioned, added in the solution of the bromo- 4- pyridine-sulfonic acids of 5- bis- after nickel powder and ethanol solution, 3~5h of back flow reaction, after cooling alkalescent is adjusted to concentration for 14~18mol/L sodium hydroxide solution, after be extracted with ethyl acetate three times, then with anhydrous sodium sulfate drying, filtering, concentration, ethyl alcohol recrystallization, obtain white solid, as 3,5- dibromo pyridines.
It is used as further scheme of the invention：The step（1）In, 4-aminopyridine is 1 with the mol ratio of N- bromo-succinimides：2.05~2.15.
It is used as further scheme of the invention：The step（1）In, react 20h.
It is used as further scheme of the invention：The step（2）In, the mol ratio of the concentrated sulfuric acid and the bromo- 4-aminopyridine of 3,5- bis- is 4.2~4.8：1, the mol ratio of nitrosylsulfuric acid and the bromo- 4-aminopyridine of 3,5- bis- is 1.3~1.6：1.
It is used as further scheme of the invention：The step（2）In, the dropping temperature of nitrosylsulfuric acid is 52 DEG C, and it is 1.2h to stop the reaction time after being added dropwise.
It is used as further scheme of the invention：The step（3）In, the consumption of nickel powder is twice of the mole of the bromo- 4-aminopyridines of 3,5- bis-.
It is used as further scheme of the invention：The step（3）In, reflux time is 4.2h.
It is used as further scheme of the invention：The step（3）In, the concentration of sodium hydroxide solution is 16mol/L.
Compared with prior art, the beneficial effects of the invention are as follows：
Reaction condition of the present invention is gentle, high income, and raw material is easy to get, and cost is relatively low, and process route is short, and product accessory substance is few, and purity is high, the cost of later stage separation is reduced, with industrial prospect.
Embodiment
Below in conjunction with the embodiment of the present invention, the technical scheme in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art are obtained under the premise of creative work is not made belongs to the scope of protection of the invention.
Embodiment 1
In the embodiment of the present invention, the synthetic method of one kind 3,5- dibromo pyridines comprises the following steps：
（1）Bromination reaction：3.76g is added in 100ml there-necked flasks（0.04mol）4-aminopyridine and 0.04g azodiisobutyronitriles are dissolved in 36ml carbon tetrachloride, and N- bromo-succinimides 14.60g is added portionwise at 25 DEG C（0.082mol）, react control in 18h, liquid phase and monitor that raw material 4-aminopyridine and the bromo- 4-aminopyridines of intermediate 3- are converted into after target product 3, the bromo- 4-aminopyridines of 5- bis-, stop reaction；Reaction solution is stirred down and is cooled to after room temperature, pour into 50ml carbon tetrachloride and stir, filter, filter cake is washed twice with 2 × 30ml carbon tetrachloride, and filtrate washed once with sodium bicarbonate aqueous solution, saturated aqueous common salt washed once, revolving eliminates carbon tetrachloride, then is recrystallized with petroleum ether, obtains 9.22g white solids, as 3, the bromo- 4-aminopyridines of 5- bis-, yield 91.50%, 161~162 DEG C of fusing point；
（2）Diazo-reaction：The concentrated sulfuric acid and 2.52g that 0.042mol concentration is 17.8mol/L are added in 200ml there-necked flask（0.01mol）3,5- bis- bromo- 4-aminopyridines, after treating that the bromo- 4-aminopyridines of 3,5- bis- are completely dissolved, 2.03g is added dropwise at 48 DEG C（0.013mol）Nitrosylsulfuric acid, reaction end is examined using potassium iodide starch test paper, is reacted 1.5h after stopping being added dropwise when reaction solution makes potassium iodide starch test paper become blue and not take off, is obtained the bromo- 4- pyridine-sulfonic acids of 3,5- bis-；
（3）Reduction reaction：1.17g is added into the above-mentioned solution containing the bromo- 4- pyridine-sulfonic acids of 3,5- bis-（0.02mol）After nickel powder, it is added dropwise after 20ml ethanol solutions, back flow reaction 5h, the sodium hydroxide solution for being 18mol/L with concentration after cooling is adjusted to alkalescent, is extracted three times with 3 × 30ml ethyl acetate afterwards, again with anhydrous sodium sulfate drying, filtering, concentration, ethyl alcohol recrystallization, obtain 1.12g white solids, as 3,5- dibromo pyridines, yield 47.28%, 112~113 DEG C of fusing point.
The total recovery of 3,5- dibromo pyridines is 91.50% × 47.28%=43.26%.
Embodiment 2
In the embodiment of the present invention, the synthetic method of one kind 3,5- dibromo pyridines comprises the following steps：
（1）Bromination reaction：3.76g is added in 100ml there-necked flasks（0.04mol）4-aminopyridine and 0.04g azodiisobutyronitriles are dissolved in 36ml carbon tetrachloride, and N- bromo-succinimides 15.31g is added portionwise at 25 DEG C（0.086mol）, react control in 22h, liquid phase and monitor that raw material 4-aminopyridine and the bromo- 4-aminopyridines of intermediate 3- are converted into after target product 3, the bromo- 4-aminopyridines of 5- bis-, stop reaction；Reaction solution is stirred down and is cooled to after room temperature, pour into 50ml carbon tetrachloride and stir, filter, filter cake is washed twice with 2 × 30ml carbon tetrachloride, and filtrate washed once with sodium bicarbonate aqueous solution, saturated aqueous common salt washed once, revolving eliminates carbon tetrachloride, then is recrystallized with petroleum ether, obtains 9.25g white solids, as 3, the bromo- 4-aminopyridines of 5- bis-, yield 91.80%, 162~163 DEG C of fusing point；
（2）Diazo-reaction：The concentrated sulfuric acid and 2.52g that 0.048mol concentration is 16.90mol/L are added in 200ml there-necked flask（0.01mol）3,5- bis- bromo- 4-aminopyridines, after treating that the bromo- 4-aminopyridines of 3,5- bis- are completely dissolved, 1.65g is added dropwise at 55 DEG C（0.013mol）Nitrosylsulfuric acid, reaction end is examined using potassium iodide starch test paper, is reacted 1h after stopping being added dropwise when reaction solution makes potassium iodide starch test paper become blue and not take off, is obtained the bromo- 4- pyridine-sulfonic acids of 3,5- bis-；
（3）Reduction reaction：1.17g is added into the above-mentioned solution containing the bromo- 4- pyridine-sulfonic acids of 3,5- bis-（0.02mol）After nickel powder, it is added dropwise after 20ml ethanol solutions, back flow reaction 3h, the sodium hydroxide solution for being 14mol/L with concentration after cooling is adjusted to alkalescent, is extracted three times with 3 × 30ml ethyl acetate afterwards, again with anhydrous sodium sulfate drying, filtering, concentration, ethyl alcohol recrystallization, obtain 1.08g white solids, as 3,5- dibromo pyridines, yield 45.59%, 111~112 DEG C of fusing point.
The total recovery of 3,5- dibromo pyridines is 91.80% × 45.59%=41.85%.
Embodiment 3
In the embodiment of the present invention, the synthetic method of one kind 3,5- dibromo pyridines comprises the following steps：
（1）Bromination reaction：3.76g is added in 100ml there-necked flasks（0.04mol）4-aminopyridine and 0.04g azodiisobutyronitriles are dissolved in 36ml carbon tetrachloride, and N- bromo-succinimides 14.95g is added portionwise at 25 DEG C（0.084mol）, react control in 20h, liquid phase and monitor that raw material 4-aminopyridine and the bromo- 4-aminopyridines of intermediate 3- are converted into after target product 3, the bromo- 4-aminopyridines of 5- bis-, stop reaction；Reaction solution is stirred down and is cooled to after room temperature, pour into 50ml carbon tetrachloride and stir, filter, filter cake is washed twice with 2 × 30ml carbon tetrachloride, and filtrate washed once with sodium bicarbonate aqueous solution, saturated aqueous common salt washed once, revolving eliminates carbon tetrachloride, then is recrystallized with petroleum ether, obtains 9.28g white solids, as 3, the bromo- 4-aminopyridines of 5- bis-, yield 92.10%, 162~163 DEG C of fusing point；
（2）Diazo-reaction：The concentrated sulfuric acid and 2.52g that 0.045mol concentration is 17.5mol/L are added in 200ml there-necked flask（0.01mol）3,5- bis- bromo- 4-aminopyridines, after treating that the bromo- 4-aminopyridines of 3,5- bis- are completely dissolved, 1.78g is added dropwise at 52 DEG C（0.014mol）Nitrosylsulfuric acid, reaction end is examined using potassium iodide starch test paper, is reacted 1.2h after stopping being added dropwise when reaction solution makes potassium iodide starch test paper become blue and not take off, is obtained the bromo- 4- pyridine-sulfonic acids of 3,5- bis-；
（3）Reduction reaction：1.17g is added into the above-mentioned solution containing the bromo- 4- pyridine-sulfonic acids of 3,5- bis-（0.02mol）After nickel powder, it is added dropwise after 20ml ethanol solutions, back flow reaction 4h, the sodium hydroxide solution for being 16mol/L with concentration after cooling is adjusted to alkalescent, is extracted three times with 3 × 30ml ethyl acetate afterwards, again with anhydrous sodium sulfate drying, filtering, concentration, ethyl alcohol recrystallization, obtain 1.15g white solids, as 3,5- dibromo pyridines, yield 48.54%, 112~113 DEG C of fusing point.
The total recovery of 3,5- dibromo pyridines is 92.10% × 48.54%=44.71%.
Reaction condition of the present invention is gentle, high income（41.85~44.71%）, and raw material is easy to get, cost is relatively low, and process route is short, and product accessory substance is few, and purity is high, the cost of later stage separation is reduced, with industrial prospect.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, and without departing from the spirit or essential characteristics of the present invention, the present invention can be realized in other specific forms.Therefore, no matter from the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is limited by appended claims rather than described above, it is intended that all changes fallen in the implication and scope of the equivalency of claim are included in the present invention.
In addition, it should be understood that, although the present specification is described in terms of embodiments, but not each embodiment is only comprising an independent technical scheme, this narrating mode of specification is only for clarity, the skilled in the art should refer to the specification as a whole, and the technical solutions in the various embodiments may also be suitably combined, and other embodiments which can be understood by those skilled in the art for formation.
Claims (8)
1. one kind 3, the synthetic method of 5- dibromo pyridines, it is characterised in that comprise the following steps：
（1）Bromination reaction：4-aminopyridine is added in there-necked flask and azodiisobutyronitrile is dissolved in carbon tetrachloride, N- bromo-succinimides are added at 25 DEG C, is reacted control monitoring in 18~22h, liquid phase and, to reacting complete, is stopped reaction；Reaction solution is stirred down and is cooled to after room temperature, pour into carbon tetrachloride and stir, filter, filter cake is washed twice with carbon tetrachloride, filtrate washed once with sodium bicarbonate aqueous solution, and saturated aqueous common salt washed once, and revolving eliminates carbon tetrachloride, recrystallized again with petroleum ether, obtain white solid, the bromo- 4-aminopyridines of as 3,5- bis-；
（2）Diazo-reaction：The concentrated sulfuric acid and 3 that concentration is 16.90~17.8mol/L is added in there-necked flask, the bromo- 4-aminopyridines of 5- bis-, treat 3, after the bromo- 4-aminopyridines of 5- bis- are completely dissolved, nitrosylsulfuric acid is added dropwise at 48~55 DEG C, reaction end is examined using potassium iodide starch test paper, 1~1.5h is reacted after stopping being added dropwise when reaction solution makes potassium iodide starch test paper become blue and not take off, obtain the bromo- 4- pyridine-sulfonic acids of 3,5- bis-；
（3）Reduction reaction：Contain 3 toward above-mentioned, added in the solution of the bromo- 4- pyridine-sulfonic acids of 5- bis- after nickel powder and ethanol solution, 3~5h of back flow reaction, after cooling alkalescent is adjusted to concentration for 14~18mol/L sodium hydroxide solution, after be extracted with ethyl acetate three times, then with anhydrous sodium sulfate drying, filtering, concentration, ethyl alcohol recrystallization, obtain white solid, as 3,5- dibromo pyridines.
2. the synthetic method of 3,5- dibromo pyridines according to claim 1, it is characterised in that the step（1）In, 4-aminopyridine is 1 with the mol ratio of N- bromo-succinimides：2.05~2.15.
3. the synthetic method of 3,5- dibromo pyridines according to claim 1, it is characterised in that the step（1）In, react 20h.
4. the synthetic method of 3,5- dibromo pyridines according to claim 1, it is characterised in that the step（2）In, the mol ratio of the concentrated sulfuric acid and the bromo- 4-aminopyridine of 3,5- bis- is 4.2~4.8：1, the mol ratio of nitrosylsulfuric acid and the bromo- 4-aminopyridine of 3,5- bis- is 1.3~1.6：1.
5. the synthetic method of 3,5- dibromo pyridines according to claim 1, it is characterised in that the step（2）In, the dropping temperature of nitrosylsulfuric acid is 52 DEG C, and it is 1.2h to stop the reaction time after being added dropwise.
6. the synthetic method of 3,5- dibromo pyridines according to claim 1, it is characterised in that the step（3）In, the consumption of nickel powder is twice of the mole of the bromo- 4-aminopyridines of 3,5- bis-.
7. the synthetic method of 3,5- dibromo pyridines according to claim 1, it is characterised in that the step（3）In, reflux time is 4.2h.
8. the synthetic method of 3,5- dibromo pyridines according to claim 1, it is characterised in that the step（3）In, the concentration of sodium hydroxide solution is 16mol/L.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115304544A (en) * | 2022-08-01 | 2022-11-08 | 童航 | Synthetic method of 5-bromo-2- (methylamino) pyridine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115304544A (en) * | 2022-08-01 | 2022-11-08 | 童航 | Synthetic method of 5-bromo-2- (methylamino) pyridine |
| CN115304544B (en) * | 2022-08-01 | 2024-02-09 | 童航 | Synthesis method of 5-bromo-2- (methylamino) pyridine |
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