CN109456322A - A kind of synthetic method of medicine intermediate 5- azaindole - Google Patents
A kind of synthetic method of medicine intermediate 5- azaindole Download PDFInfo
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- CN109456322A CN109456322A CN201811329178.5A CN201811329178A CN109456322A CN 109456322 A CN109456322 A CN 109456322A CN 201811329178 A CN201811329178 A CN 201811329178A CN 109456322 A CN109456322 A CN 109456322A
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- azaindole
- aminopyridine
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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 methods of medicine intermediate 5- azaindole, the following steps are included: after 3- methyl -4-aminopyridine is mixed with acetone, it is heated to 40-60 DEG C, oxalate is added thereto after catalyst is added, and under stirring condition, carries out back flow reaction 1-2h, filtering, filtrate is evaporated under reduced pressure, is recrystallized, 4-aminopyridine -3- pyruvate is made；It is added into DMA, salicylic acid is added and is stirring evenly and then adding into FeO, is heated to 60-70 DEG C, be stirred at reflux reaction 2-3h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- formic acid is made；After it is mixed with carbon tetrachloride, it is heated to 70-90 DEG C, ZnO is added and is uniformly mixed, after being stirred at reflux reaction 2-3h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.The synthetic method of the application is easy to operate, and mild condition, by-product is less, and product purity is high, and product yield is higher.
Description
Technical field
The present invention relates to medicine intermediate fields, more particularly to a kind of synthesis side of medicine intermediate 5- azaindole
Method.
Background technique
Benzazole compounds are one of heterocyclic compound important branch, are natures with multiple biological activities
The middle most commonly used heterocyclic compound of distribution.Benzazole compounds are important Organic Chemicals and product, can be used as doctor
Medicine, pesticide, dyestuff, fragrance and other fine chemical products intermediate, had a wide range of applications in multiple fields.Azaindole
It can regard the bioisostere of indoles as, so azaindoles are in pharmaceutical activity MOLECULE DESIGN and synthesis side
Face plays an important role.In terms of pharmacological action, azaindoles have anticancer, antibacterial, antiviral, treatment height
The purposes such as blood pressure.Wherein, 5- azaindole is compound important in azaindole.5- azaindole is by indole ring 5
Carbon atom on key is replaced into nitrogen-atoms, so that 5- azaindole and indoles change in structure, physicochemical properties
It is all different from indoles, it is a kind of very valuable intermediate.5- azaindole has certain inhibiting effect to kinases, can be used for
Treat the diseases such as cardiovascular disease, inflammation, central nervous system confusion and diabetes.
At present according to reports, about 5- azaindole synthetic method mainly include the following types: 1, with 4- amino -3- bromopyridine
For raw material, by palladium chtalyst, then cyclization generates 5- azaindole under acid condition again, and this method reaction time consumption is too long, produces this
Higher, yield is lower；2, using 3- methyl -4- nitrate pyridine oxide as raw material, respectively at DMA, morpholine methane, orthoformic acid second
The reactions such as ester generate enamine, and then 5- azaindole is made in raney ni catalysis hydrogenating reduction, and this method reaction is insufficient, need big
Catalyst is measured, cost is increased, and yield is undesirable.These existing methods all still have several drawbacks, therefore, research and develop it is a kind of efficiently,
The preparation method of 5- azaindole easy to operate has great importance.
Chinese patent CN201210150087.1 discloses a kind of preparation method of 5- azaindole, and the invention is with 3- methyl
Pyridine is raw material, including following five steps: (1) 3- picoline occurs oxidation reaction, obtains 3- first under the action of oxidant
Yl pyridines nitrogen oxides.(2) 3- methyl pyridine nitrogen oxide occurs nitration reaction, obtains 3- methyl -4- under the action of nitration mixture
Nitropyridine nitrogen oxides.(3) 3- methyl -4- nitropyridine nitrogen oxides reacts in a solvent with phosphorus trichloride, obtains 3- first
Base -4- nitropyridine.(4) 3- methyl -4- nitropyridine is in solvent n,N-Dimethylformamide, with n,N-Dimethylformamide
Contracting dialkyl acetal reacts under heating conditions, obtains 3- dialkylamine vinyl -4- nitropyridine.(5) 3- dioxane
Base amine vinyl -4- nitropyridine carries out reduction reaction under the action of metallic catalyst, and cyclization simultaneously, obtains final products
5- azaindole.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of medicine intermediate 5- azaindole, synthetic method operation letters
Single, mild condition, by-product is less, and product purity is high, and product yield is higher.
To achieve the above object, the invention adopts the following technical scheme:
A kind of synthetic method of medicine intermediate 5- azaindole, comprising the following steps:
(1) after mixing 3- methyl -4-aminopyridine with acetone, it is heated to 40-60 DEG C, is added after catalyst and adds thereto
Enter oxalate, under stirring condition, carry out back flow reaction 1-2h, filtrate is evaporated under reduced pressure by filtering, recrystallizes, and 4- ammonia is made
Yl pyridines -3- pyruvate；
(2) 4-aminopyridine -3- pyruvate obtained is added in DMA, salicylic acid is added and is stirring evenly and then adding into
FeO is heated to 60-70 DEG C, is stirred at reflux reaction 2-3h, and filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- is made
Formic acid；
(3) after mixing the 5- azaindole -2- formic acid of preparation with carbon tetrachloride, it is heated to 70-90 DEG C, it is mixed that ZnO is added
It closes uniformly, after being stirred at reflux reaction 2-3h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.
Preferably, it is 1:1.5-1.9 that 3- methyl -4-aminopyridine and oxalate, which use molar ratio, in the step (1).
Preferably, catalyst is TiCl in the step (1)2(ClO4)2。
Preferably, the mass ratio that uses of 3- methyl -4-aminopyridine and catalyst is 8:1 in the step (1).
Preferably, 4-aminopyridine -3- pyruvate and salicylic molar ratio are 1:1.8-2.3 in the step (2)；
Preferably, the use molar ratio of 4-aminopyridine -3- pyruvate and FeO are 1:0.4- in the step (2)
0.7。
Preferably, the usage amount molar ratio of 5- azaindole -2- formic acid and ZnO are 17:6 in the step (3).
5- azaindole is prepared by raw material of 3- methyl -4-aminopyridine the invention has the advantages that using,
Middle 3- methyl -4-aminopyridine is cheap and easy to get, so that lower production costs.The present invention utilizes TiCl2(ClO4)2It is catalyzed 3- methyl-
4-aminopyridine is reacted with oxalate, and the reaction process is selectively strong, high-efficient, conversion ratio with higher, and product is received
Rate is high.Preparation method of the invention is easy to operate, and process flow is shorter, and by-product is less, and product postprocessing is relatively simple, very
It is suitble to large-scale industrial production.
Specific embodiment
In order to better understand the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving
The present invention is released, any restriction will not be constituted to the present invention.
Embodiment 1
A kind of synthetic method of 5- azaindole, comprising the following steps:
(1) after mixing 3- methyl -4-aminopyridine with acetone, 40 DEG C are heated to, catalyst TiCl is added2(ClO4)2Afterwards
It is added oxalate thereto, under stirring condition, carries out back flow reaction 1h, filtrate is evaporated under reduced pressure by filtering, recrystallizes, system
Obtain 4-aminopyridine -3- pyruvate；
(2) 4-aminopyridine -3- pyruvate obtained is added in DMA, salicylic acid is added and is stirring evenly and then adding into
FeO is heated to 60 DEG C, is stirred at reflux reaction 2h, and filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- formic acid is made；
(3) after mixing the 5- azaindole -2- formic acid of preparation with carbon tetrachloride, 70 DEG C are heated to, ZnO mixing is added
Uniformly, after being stirred at reflux reaction 2h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.
It is 1:1.5 that 3- methyl -4-aminopyridine and oxalate, which use molar ratio, in step (1)；3- methyl -4-aminopyridine
The mass ratio that uses with catalyst is 8:1.
4-aminopyridine -3- pyruvate and salicylic molar ratio are 1:1.8 in step (2)；4-aminopyridine -3- third
The use molar ratio of keto ester and FeO are 1:0.4.
The usage amount molar ratio of 5- azaindole -2- formic acid and ZnO are 17:6 in step (3).
The yield of 5- azaindole obtained is 90.1%, purity 99.4%；1H NMR (600MHz, CDCl3), δ:
11.16 (s, 1H, NH), 8.95 (s, 1H), 8.25 (d, J=4.9Hz, 1H), 7.32 (d, J=4.9Hz, 1H), 7.33 (d, J=
3.1Hz, 1H), 6.66 (d, J=3.1Hz, 1H).
Embodiment 2
A kind of synthetic method of 5- azaindole, comprising the following steps:
(1) after mixing 3- methyl -4-aminopyridine with acetone, 60 DEG C are heated to, catalyst TiCl is added2(ClO4)2Afterwards
It is added oxalate thereto, under stirring condition, carries out back flow reaction 2h, filtrate is evaporated under reduced pressure by filtering, recrystallizes, system
Obtain 4-aminopyridine -3- pyruvate；
(2) 4-aminopyridine -3- pyruvate obtained is added in DMA, salicylic acid is added and is stirring evenly and then adding into
FeO is heated to 70 DEG C, is stirred at reflux reaction 3h, and filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- formic acid is made；
(3) after mixing the 5- azaindole -2- formic acid of preparation with carbon tetrachloride, 90 DEG C are heated to, ZnO mixing is added
Uniformly, after being stirred at reflux reaction 3h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.
It is 1:1.9 that 3- methyl -4-aminopyridine and oxalate, which use molar ratio, in step (1)；3- methyl -4-aminopyridine
The mass ratio that uses with catalyst is 8:1.
4-aminopyridine -3- pyruvate and salicylic molar ratio are 1:2.3 in step (2)；4-aminopyridine -3- third
The use molar ratio of keto ester and FeO are 1:0.7.
The usage amount molar ratio of 5- azaindole -2- formic acid and ZnO are 17:6 in step (3).
The yield of 5- azaindole obtained is 90.3%, purity 99.3%.
Embodiment 3
A kind of synthetic method of 5- azaindole, comprising the following steps:
(1) after mixing 3- methyl -4-aminopyridine with acetone, 40 DEG C are heated to, catalyst TiCl is added2(ClO4)2Afterwards
It is added oxalate thereto, under stirring condition, carries out back flow reaction 2h, filtrate is evaporated under reduced pressure by filtering, recrystallizes, system
Obtain 4-aminopyridine -3- pyruvate；
(2) 4-aminopyridine -3- pyruvate obtained is added in DMA, salicylic acid is added and is stirring evenly and then adding into
FeO is heated to 60 DEG C, is stirred at reflux reaction 3h, and filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- formic acid is made；
(3) after mixing the 5- azaindole -2- formic acid of preparation with carbon tetrachloride, 70 DEG C are heated to, ZnO mixing is added
Uniformly, after being stirred at reflux reaction 3h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.
It is 1:1.5 that 3- methyl -4-aminopyridine and oxalate, which use molar ratio, in step (1)；3- methyl -4-aminopyridine
The mass ratio that uses with catalyst is 8:1.
4-aminopyridine -3- pyruvate and salicylic molar ratio are 1:2.3 in step (2)；4-aminopyridine -3- third
The use molar ratio of keto ester and FeO are 1:0.4.
The usage amount molar ratio of 5- azaindole -2- formic acid and ZnO are 17:6 in step (3).
The yield of 5- azaindole obtained is 91.1%, purity 99.2%.
Embodiment 4
A kind of synthetic method of 5- azaindole, comprising the following steps:
(1) after mixing 3- methyl -4-aminopyridine with acetone, 60 DEG C are heated to, catalyst TiCl is added2(ClO4)2Afterwards
It is added oxalate thereto, under stirring condition, carries out back flow reaction 1h, filtrate is evaporated under reduced pressure by filtering, recrystallizes, system
Obtain 4-aminopyridine -3- pyruvate；
(2) 4-aminopyridine -3- pyruvate obtained is added in DMA, salicylic acid is added and is stirring evenly and then adding into
FeO is heated to 70 DEG C, is stirred at reflux reaction 2h, and filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- formic acid is made；
(3) after mixing the 5- azaindole -2- formic acid of preparation with carbon tetrachloride, 90 DEG C are heated to, ZnO mixing is added
Uniformly, after being stirred at reflux reaction 2h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.
It is 1:1.9 that 3- methyl -4-aminopyridine and oxalate, which use molar ratio, in step (1)；3- methyl -4-aminopyridine
The mass ratio that uses with catalyst is 8:1.
4-aminopyridine -3- pyruvate and salicylic molar ratio are 1:1.8 in step (2)；4-aminopyridine -3- third
The use molar ratio of keto ester and FeO are 1:0.7.
The usage amount molar ratio of 5- azaindole -2- formic acid and ZnO are 17:6 in step (3).
The yield of 5- azaindole obtained is 91.4%, purity 99.2%.
Embodiment 5
A kind of synthetic method of 5- azaindole, comprising the following steps:
(1) after mixing 3- methyl -4-aminopyridine with acetone, 50 DEG C are heated to, catalyst TiCl is added2(ClO4)2Afterwards
It is added oxalate thereto, under stirring condition, carries out back flow reaction 1h, filtrate is evaporated under reduced pressure by filtering, recrystallizes, system
Obtain 4-aminopyridine -3- pyruvate；
(2) 4-aminopyridine -3- pyruvate obtained is added in DMA, salicylic acid is added and is stirring evenly and then adding into
FeO is heated to 65 DEG C, is stirred at reflux reaction 3h, and filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- formic acid is made；
(3) after mixing the 5- azaindole -2- formic acid of preparation with carbon tetrachloride, 80 DEG C are heated to, ZnO mixing is added
Uniformly, after being stirred at reflux reaction 2h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.
It is 1:1.7 that 3- methyl -4-aminopyridine and oxalate, which use molar ratio, in step (1)；3- methyl -4-aminopyridine
The mass ratio that uses with catalyst is 8:1.
4-aminopyridine -3- pyruvate and salicylic molar ratio are 1:2.1 in step (2)；4-aminopyridine -3- third
The use molar ratio of keto ester and FeO are 1:0.6.
The usage amount molar ratio of 5- azaindole -2- formic acid and ZnO are 17:6 in step (3).
The yield of 5- azaindole obtained is 90.2%, purity 99.4%.
Claims (7)
1. a kind of synthetic method of medicine intermediate 5- azaindole, it is characterised in that: the following steps are included:
(1) after mixing 3- methyl -4-aminopyridine with acetone, it is heated to 40-60 DEG C, is added after catalyst and grass is added thereto
Acid esters under stirring condition, carries out back flow reaction 1-2h, and filtrate is evaporated under reduced pressure by filtering, recrystallizes, and 4- amino pyrrole is made
Pyridine -3- pyruvate；
(2) 4-aminopyridine -3- pyruvate obtained is added in DMA, salicylic acid is added and is stirring evenly and then adding into FeO, adds
Heat is stirred at reflux reaction 2-3h to 60-70 DEG C, and filtrate is evaporated under reduced pressure by filtering, and 5- azaindole -2- formic acid is made；
(3) after mixing the 5- azaindole -2- formic acid of preparation with carbon tetrachloride, it is heated to 70-90 DEG C, it is equal that ZnO mixing is added
Even, after being stirred at reflux reaction 2-3h, filtrate is evaporated under reduced pressure by filtering, and 5- azaindole is made.
2. the synthetic method of medicine intermediate 5- azaindole according to claim 1, it is characterised in that: the step
(1) it is 1:1.5-1.9 that 3- methyl -4-aminopyridine and oxalate, which use molar ratio, in.
3. the synthetic method of medicine intermediate 5- azaindole according to claim 1, it is characterised in that: the step
(1) catalyst is TiCl in2(ClO4)2。
4. the synthetic method of medicine intermediate 5- azaindole according to claim 1, it is characterised in that: the step
(1) mass ratio that uses of 3- methyl -4-aminopyridine and catalyst is 8:1 in.
5. the synthetic method of medicine intermediate 5- azaindole according to claim 1, it is characterised in that: the step
(2) 4-aminopyridine -3- pyruvate and salicylic molar ratio are 1:1.8-2.3 in.
6. the synthetic method of medicine intermediate 5- azaindole according to claim 1, it is characterised in that: the step
(2) the use molar ratio of 4-aminopyridine -3- pyruvate and FeO are 1:0.4-0.7 in.
7. the synthetic method of medicine intermediate 5- azaindole according to claim 1, it is characterised in that: the step
(3) the usage amount molar ratio of 5- azaindole -2- formic acid and ZnO are 17:6 in.
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