CN105646486B - A kind of synthetic method of 5 azaindole - Google Patents
A kind of synthetic method of 5 azaindole Download PDFInfo
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- CN105646486B CN105646486B CN201610114723.3A CN201610114723A CN105646486B CN 105646486 B CN105646486 B CN 105646486B CN 201610114723 A CN201610114723 A CN 201610114723A CN 105646486 B CN105646486 B CN 105646486B
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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 discloses a kind of synthetic method of 5 azaindole, using the nitrate pyridine oxide of 3 methyl 4 as initiation material, first generate enamine, pass through zinc/copper sulfate solution reduction system again, synthesize 5 azaindoles, the synthetic reaction shortens the reaction time, and course of reaction is stable, high income, reduces cost, with higher economic benefit.
Description
Technical field：
The present invention relates to a kind of synthetic method of 5- azaindoles, belong to the field of chemical synthesis.
Background technology：
Azaindole is the important intermediate of fine chemical product, in fields such as medicine, food, agricultural chemicals, household chemicals
There is extensive purposes, the synthesis of indole derivatives is also a big focus of organic chemistry filed.Although having there is many height
The method for imitating synthesis of indole derivative, because azaindole differs structurally from indoles, so some classical synthesis of indole
Method be not readily applicable to the synthesis of azaindole.In azaindoles, 5- azaindoles are more difficult to synthesis, a lot
The method of classical synthesis of indole ring and synthesize the methods of other azaindoles and can not all synthesize 5 azaindoles well.Cause
This, the synthetic method progress research to 5- azaindoles is necessary.
Mainly have following several on synthesizing the method for 5 azaindoles both at home and abroad at present：
One is for Material synthesis with 4- amino -3- bromopyridines (or 4- amino -3- chloropyridines, 4- amino -3- iodine pyridines)
5- azaindoles.
Two be, from 4- amino -3- bromopyridines, to be reacted by the Stille of palladium chtalyst, then cyclic in acid condition
5- azaindoles are generated, but its reaction time is long, yield is low, and synthesis cost is high.
Three be by ethoxyacetylene and 4, with 4- amino -3- bromine pyrroles after the reaction of 4,5,5- tetramethyl -1,3- dioxaborinates
5- azaindoles are obtained after pyridine reaction.But chlorine or bromine atom, in meta, activation capacity is small；The second is amino is in contraposition, conjugation
Effect makes its alkalescence enhancing, and yield is relatively low.
Four be using 3- methyl -4- nitrates pyridine oxides as raw material, using Leimgruber-Batcho indole synthesis
To prepare 5- azaindoles.But this method produces methanol, low boiling point reduces reaction temperature, and reaction is incomplete, and needs big
The Raney's nickel catalyst of amount.
Happiness, weighing apparatus woods is gloomy in periodical《Chemical research and application》The 4th phase of volume 27 in April, 2015, disclose a name
For《The Study of synthesis method of 5- azaindoles》Document, text is using 3- methyl -4- nitrates pyridine oxides as initiation material, through two steps
Reaction synthesis 5- azaindoles.Temperature, DMF, N, N- dimethyl formyls have studied by experiments of single factor
Influence of the factors such as amine dimethylacetal, iron powder to reaction, under the conditions of preferred process, product presses 3- methyl -4- nitropyridine nitrogen
Oxide meter total recovery is 88.57%, and short with the reaction time simple to operate, cost is low, the advantage of high income, is of the invention
Closest to prior art.But the reduction system less stable that its iron powder is constituted with acetic acid is, it is necessary to which the temperature increased could reach
To preferable reduction effect, high energy consumption is caused, reaction efficiency is low.
The synthetic route of this method is as follows：
The content of the invention：
Technical problem solved by the invention：
The present invention is optimized to the course of reaction of prior art, improves the reaction speed and product yield of synthetic reaction,
Optimize course of reaction, reduction synthesis cost is increased economic efficiency.
The present invention provides following technical scheme：
A kind of synthetic method of 5- azaindoles, using 3- methyl -4- nitrates pyridine oxides as initiation material, first generates alkene
Amine, then by reduction reaction, generate 5- azaindoles, including following operating procedure：
The first step：3.08g3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask,
12mLDMF, 10mLDMA, are placed in oil bath pan, are warming up to 110-120 DEG C, back flow reaction 20 minutes；Subtract after the cooling of question response liquid
Pressure steams solvent, adds 10mL absolute ethyl alcohols, and solid washing and drying is obtained 3- decil alkenyl -4- nitropyridines by suction filtration
Nitrogen oxides；
Second step：3.00g3- decil alkenyl -4- nitropyridine nitrogen oxides is added in 100mL pear-shaped flask
With 30mL copper sulfate solution, lower addition zinc powder is stirred at room temperature；50 DEG C are warming up to, complete 5-7 minutes is reacted；Question response liquid
After cooling, it is extracted with ethyl acetate, organic layer is evaporated, recrystallized with water, suction filtration, drying obtains 5- azaindoles.
It is preferred that, 3- methyl -4- nitropyridine nitrogen oxidations are sequentially added in the first step in 100mL round-bottomed flask
Thing, DMF, DMA are placed in oil bath pan, are warming up to 120 DEG C, back flow reaction.
It is preferred that, 3- methyl -4- nitropyridine nitrogen oxidations are sequentially added in the first step in 100mL round-bottomed flask
Thing, DMF, DMA are placed in oil bath pan, are warming up to 110 DEG C, back flow reaction.
It is preferred that, the mass concentration of copper sulfate solution is 5-8% in the second step.
It is preferred that, the addition of zinc powder is 1g in the second step.
The synthetic route that the present invention reacts is：
3- decil alkenyl -4- nitropyridines nitrogen oxides is in iron/aqueous acetic acid reduction system, temperature rise,
Reaction yield increases, but after reaction temperature rises to 75 DEG C, yield is not further added by；The consumption of increase iron powder can improve reaction
Yield, but when 3- decil alkenyl -4- nitropyridines nitrogen oxides is 3g, add after iron powder 8.5g, continue to increase iron powder
Consumption, reaction yield is not further added by；When the ratio of acetic acid and water is 1: 9, reaction yield highest, in the system, yield highest
For 91.41%.
In iron/aqueous acetic acid reduction system, while carrying out two reactions, first is that acetic acid reacts with iron：
2HAc+Fe=Fe (Ac) 2+H2 ↑
Ferrous acetate is oxidized by oxygen again：
4Fe (Ac) 2+4HAc+O2=Fe (Ac) 3+2H2O
Then because acetic acid is acid too weak, ferric acetate hydrolysis：
Fe (Ac) 3+3H2O=Fe (OH) 3+3HAc
The colloidal iron hydroxide ultimately produced；
Second reaction is that acetic acid oxygen and iron can react：
12HAc+3O2+4Fe=4Fe (Ac) 3+6H2O
Reaction is hydrolyzed in Fe (Ac) 3 simultaneously, and the latter does not have due to oxygen and acetic acid and the iron directly reaction dissolved in solution
There is gas generation, it should be that two reactions are simultaneous, reaction is complicated and slow, potential change is smaller and changes unstable,
Cause 3- decil alkenyl -4- nitropyridines nitrogen oxides reaction yield in the reduction system relatively low.
In zinc/copper sulphate reduction system, reaction is slow uniform, and carries out exothermic phenomenon with reaction, accelerates 3- bis-
Methylamine vinyl -4- nitropyridines nitrogen oxides reaction yield in the reduction system, increases economic efficiency.
Beneficial effects of the present invention：
1. the present invention is optimized to the course of reaction of prior art, the reaction speed and finished product for improving synthetic reaction are received
Rate, optimizes course of reaction, and reduction synthesis cost is increased economic efficiency.
2. the easily controllable reaction of synthetic method of the present invention is carried out, high for reaction condition control property, be conducive to extensive work
Industry is promoted.
Embodiment：
Embodiments of the invention are described in detail below, the present embodiment is carried out lower premised on inventive technique scheme
Implement, give detailed embodiment and specific operating process, but protection scope of the present invention is not limited to following realities
Apply example.The experimental program of unreceipted actual conditions in embodiment, generally according to the condition proposed by normal condition or manufacturer
Implement.
Embodiment one：
A kind of synthetic method of 5- azaindoles, using 3- methyl -4- nitrates pyridine oxides as initiation material, first generates alkene
Amine, then by reduction reaction, generate 5- azaindoles, including following operating procedure：
The first step：3.08g3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask,
12mLDMF, 10mLDMA, are placed in oil bath pan, are warming up to 110 DEG C, back flow reaction 20 minutes；Depressurize and steam after the cooling of question response liquid
Go out solvent, add 10mL absolute ethyl alcohols, solid washing and drying is obtained 3- decil alkenyl -4- nitropyridine nitrogen oxygen by suction filtration
Compound；
Second step：3.00g3- decil alkenyl -4- nitropyridine nitrogen oxides is added in 100mL pear-shaped flask
With 30mL copper sulfate solution (mass concentration is 5%), lower addition zinc powder 1g is stirred at room temperature；It is warming up to 50 DEG C, reaction complete 5
Minute；After the cooling of question response liquid, it is extracted with ethyl acetate, organic layer is evaporated, recrystallized with water, suction filtration, drying obtains 5-
Azaindole.
Experiment two
A kind of synthetic method of 5- azaindoles, using 3- methyl -4- nitrates pyridine oxides as initiation material, first generates alkene
Amine, then by reduction reaction, generate 5- azaindoles, including following operating procedure：
The first step：3.08g3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask,
12mLDMF, 10mLDMA, are placed in oil bath pan, are warming up to 120 DEG C, back flow reaction 20 minutes；Depressurize and steam after the cooling of question response liquid
Go out solvent, add 10mL absolute ethyl alcohols, solid washing and drying is obtained 3- decil alkenyl -4- nitropyridine nitrogen oxygen by suction filtration
Compound；
Second step：3.00g3- decil alkenyl -4- nitropyridine nitrogen oxides is added in 100mL pear-shaped flask
With 30mL copper sulfate solution (mass concentration is 8%), lower addition zinc powder 1g is stirred at room temperature；It is warming up to 50 DEG C, reaction complete 7
Minute；After the cooling of question response liquid, it is extracted with ethyl acetate, organic layer is evaporated, recrystallized with water, suction filtration, drying obtains 5-
Azaindole.
Experiment three
A kind of synthetic method of 5- azaindoles, using 3- methyl -4- nitrates pyridine oxides as initiation material, first generates alkene
Amine, then by reduction reaction, generate 5- azaindoles, including following operating procedure：
The first step：3.08g3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask,
12mLDMF, 10mLDMA, are placed in oil bath pan, are warming up to 110 DEG C, back flow reaction 20 minutes；Depressurize and steam after the cooling of question response liquid
Go out solvent, add 10mL absolute ethyl alcohols, solid washing and drying is obtained 3- decil alkenyl -4- nitropyridine nitrogen oxygen by suction filtration
Compound；
Second step：3.00g3- decil alkenyl -4- nitropyridine nitrogen oxides is added in 100mL pear-shaped flask
With 30mL copper sulfate solution (mass concentration is 5%), lower addition zinc powder 1g is stirred at room temperature；It is warming up to 50 DEG C, reaction complete 7
Minute；After the cooling of question response liquid, it is extracted with ethyl acetate, organic layer is evaporated, recrystallized with water, suction filtration, drying obtains 5-
Azaindole.
Experiment four
A kind of synthetic method of 5- azaindoles, using 3- methyl -4- nitrates pyridine oxides as initiation material, first generates alkene
Amine, then by reduction reaction, generate 5- azaindoles, including following operating procedure：
The first step：3.08g3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask,
12mLDMF, 10mLDMA, are placed in oil bath pan, are warming up to 120 DEG C, back flow reaction 20 minutes；Depressurize and steam after the cooling of question response liquid
Go out solvent, add 10mL absolute ethyl alcohols, solid washing and drying is obtained 3- decil alkenyl -4- nitropyridine nitrogen oxygen by suction filtration
Compound；
Second step：3.00g3- decil alkenyl -4- nitropyridine nitrogen oxides is added in 100mL pear-shaped flask
With 30mL copper sulfate solution (mass concentration is 8%), lower addition zinc powder 1g is stirred at room temperature；It is warming up to 50 DEG C, reaction complete 5
Minute；After the cooling of question response liquid, it is extracted with ethyl acetate, organic layer is evaporated, recrystallized with water, suction filtration, drying obtains 5-
Azaindole.
Experiment five
A kind of synthetic method of 5- azaindoles, using 3- methyl -4- nitrates pyridine oxides as initiation material, first generates alkene
Amine, then by reduction reaction, generate 5- azaindoles, including following operating procedure：
The first step：3.08g3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask,
12mLDMF, 10mLDMA, are placed in oil bath pan, are warming up to 115 DEG C, back flow reaction 20 minutes；Depressurize and steam after the cooling of question response liquid
Go out solvent, add 10mL absolute ethyl alcohols, solid washing and drying is obtained 3- decil alkenyl -4- nitropyridine nitrogen oxygen by suction filtration
Compound；
Second step：3.00g3- decil alkenyl -4- nitropyridine nitrogen oxides is added in 100mL pear-shaped flask
With 30mL copper sulfate solution (mass concentration is 6%), lower addition zinc powder 1g is stirred at room temperature；It is warming up to 50 DEG C, reaction complete 6
Minute；After the cooling of question response liquid, it is extracted with ethyl acetate, organic layer is evaporated, recrystallized with water, suction filtration, drying is obtained
5- azaindoles.
Experiment one
The synthesis yield of 3- decil alkenyl -4- nitropyridine nitrogen oxides, by the present invention closest to prior art institute
The method of stating is denoted as comparative example, and the above embodiment of the present invention method is denoted as embodiment, testing example and comparative example 3- decils
The synthesis yield of alkenyl -4- nitropyridine nitrogen oxides, test result is shown in Table one.
Table one：The synthesis yield of 3- decil alkenyl -4- nitropyridine nitrogen oxides
| Embodiment | The synthesis yield (%) of 3- decil alkenyl -4- nitropyridine nitrogen oxides |
| Embodiment one | 97.64 |
| Embodiment two | 97.28 |
| Embodiment three | 98.51 |
| Example IV | 97.66 |
| Embodiment five | 96.64 |
| Comparative example | 96.89 |
Embodiment improves DMF addition compared with comparative example, reduces reaction temperature, its 3- decil alkenyl -4- nitre
The synthesis yield of yl pyridines nitrogen oxides is improved.
Experiment two：
The synthesis yield of the synthesis yield of 5- azaindoles, testing example and comparative example 5- azaindoles, test result
It is shown in Table two.
Table two：Embodiment and comparative example chlorizate yield
Above content is only the better embodiment of the present invention, for one of ordinary skill in the art, according to the present invention
Thought, will change in specific embodiments and applications, this specification content should not be construed as to this hair
Bright limitation.
Claims (3)
1. a kind of synthetic method of 5- azaindoles, using 3- methyl -4- nitrates pyridine oxides as initiation material, first generates alkene
Amine, then by reduction reaction, generate 5- azaindoles, it is characterised in that：Including following operating procedure：
The first step：Sequentially add 3.08g3- methyl -4- nitropyridine nitrogen oxides in 100mL round-bottomed flask, 12mLDMF,
10mLDMA, is placed in oil bath pan, is warming up to 120 DEG C, back flow reaction 20 minutes；Decompression steams solvent after the cooling of question response liquid, plus
Enter 10mL absolute ethyl alcohols, solid washing and drying is obtained 3- decil alkenyl -4- nitropyridine nitrogen oxides by suction filtration；
Second step：In 100mL pear-shaped flask add 3.00g3- decil alkenyl -4- nitropyridines nitrogen oxides and
30mL copper sulfate solution, is stirred at room temperature lower addition zinc powder；50 DEG C are warming up to, complete 5-7 minutes is reacted；Question response liquid is cooled down
Afterwards, it is extracted with ethyl acetate, organic layer is evaporated, recrystallized with water, suction filtration, drying obtains 5- azaindoles；
The mass concentration of copper sulfate solution is 5-8% in the second step；The addition of zinc powder is 1g in the second step.
2. a kind of synthetic method of 5- azaindoles according to claim 1, it is characterised in that：In the first step
3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask, DMF, DMA are placed in oil bath pan, heated up
To 120 DEG C, back flow reaction.
3. a kind of synthetic method of 5- azaindoles according to claim 1, it is characterised in that：In the first step
3- methyl -4- nitropyridine nitrogen oxides is sequentially added in 100mL round-bottomed flask, DMF, DMA are placed in oil bath pan, heated up
To 110 DEG C, back flow reaction.
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| FR2564836B1 (en) * | 1984-05-25 | 1986-09-26 | Sanofi Sa | PROCESS FOR THE PREPARATION OF AZA-5 INDOLE AND COMPOUND OBTAINED BY THIS PROCESS |
| CN1321118C (en) * | 2005-08-02 | 2007-06-13 | 浙江大学 | 5-aza-indole preparation method |
| CN103130717B (en) * | 2011-11-29 | 2015-04-01 | 上海博康精细化工有限公司 | Preparation method of 2-benzo diazepine anthrone |
| CN103980273A (en) * | 2014-06-03 | 2014-08-13 | 重庆邮电大学 | Preparation method of 5-azaindole |
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