CN106432233B - The preparation method of N, N, 6- trimethyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides - Google Patents
The preparation method of N, N, 6- trimethyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides Download PDFInfo
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- CN106432233B CN106432233B CN201610836205.2A CN201610836205A CN106432233B CN 106432233 B CN106432233 B CN 106432233B CN 201610836205 A CN201610836205 A CN 201610836205A CN 106432233 B CN106432233 B CN 106432233B
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- 0 CC*(C)c(cc1)ccc1-c1c(CC(N(*)*)=O)[n](cc(*)cc2)c2n1 Chemical compound CC*(C)c(cc1)ccc1-c1c(CC(N(*)*)=O)[n](cc(*)cc2)c2n1 0.000 description 3
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- C—CHEMISTRY; METALLURGY
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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 present invention relates to a kind of preparation methods of 2 (4 aminomethyl phenyl) imidazo [1,2 a] pyridine of N, N, 6 trimethyl, 3 acetamide, which is characterized in that the preparation method includes step:By 6 methyl 2 (4 aminomethyl phenyl) imidazos [1 under the action of condensing agent, 2 a] pyridine 3 acetic acid (2) and dimethylamine salt carry out amidation process, obtain N, N, 6 trimethyl 2 (4 aminomethyl phenyl) imidazo [1,2 a] pyridine, 3 acetamide (1).The preparation method of the present invention uses market dimethylamine salt cheap and easy to get as raw material, and 3 acetamide (1) of N, N, 6 trimethyl 2 (4 aminomethyl phenyl) imidazo [1,2 a] pyridine of high-purity is made in a step in high yield;The inventory of dimethylamine salt has saved raw material close to theoretical amount, avoids environmental pollution;The sour gas of any hostile environment is not released in reaction, reaction step is short, easy to operate, process stabilizing, safely controllable;Unique " useless solid " DCU is generated in reaction to be fully recycled, and cleanly production may be implemented.
Description
Technical field
The present invention relates to pharmaceutical preparation fields, particularly, are related to a kind of N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazoles
And the preparation method of [1,2-a] pyridine -3- acetamides.
Background technology
N, N, 6- trimethyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides (1) are also referred to as zolpidem
(Zolpidem), structural formula is as follows:
Zolpidem selectively and the combination of the ω 1-- receptor subtypes of central nervous system can generate pharmacological action, the medicine
It is developed by French Synthelabo companies, in Initial Public Offering in 1988, trade name Stilnox (Stilnox) can be used for treating tight
The disease of weight sleep disturbance, such as:Sporadic insomnia, transient insomnia.To primary insomnia and depression, mental disease
The curative effect that caused insomnia also has comparison notable.Compared with the drug of other treatment insomnia, have effect good, half-life short,
The features such as metabolism is fast, does not generate active metabolite, Small side effects, withdrawal is without rebound effect is most popular at present calmness
One of somnifacient.
The representative preparation method of (1) disclosed in the prior art has:
Arkivoc online Journal of Organic Chemistry,2009,42(3):Disclosed in 315-320
Synthetic route is first by 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acids (2) first in DCM (dichloromethanes
Alkane) in solvent with PCl5(phosphorus pentachloride) reaction is converted to highly active acyl chlorides (3), then with large excess of free diformazan
Amine condensation prepares N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides (1).Its tool synthesized
Body route is as follows:
PCl in the preparation method5With toxicity, chance water heat release is apparent, or even explodes, and there are many peaces for industrial production
Full hidden danger;A large amount of sour gas HCl is generated in reaction and phosphorus-containing wastewater, environmental hazard are big;Feeding intake for dimethylamine is significantly excessive
Not only increase material loss, but also increase the harm to environment.
Synthetic route disclosed in US4382938 is with 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3-
Acetic acid (2) is raw material, and in THF solvents, Viability stronger acylimidazole is converted with CDI (N, N '-carbonyl dimidazoles) reactions
(4), N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2- then are prepared with large excess of free dimethylamine condensation
A] pyridine -3- acetamides (1).The specific route that it is synthesized is as follows:
CDI is expensive in the preparation method, is sensitivity to water electrode, and technique is unstable, and yield is relatively low, and it is raw to be not suitable for industry
Production;The significantly excessive i.e. increase material loss that feeds intake of dimethylamine, and increase the harm to environment.
Synthetic route disclosed in WO0138327 and WO2004/087703 is with 6- methyl -2- (4- aminomethyl phenyls) imidazoles
And [1,2-a] pyridine-3-acetic acid (2) is raw material, is first reacted in methyl alcohol with thionyl chloride and 6- methyl -2- (4- methylbenzenes are made
Base) imidazo [1,2-a] pyridine-3-acetic acid methyl esters (5), then N, N, 6- tri- are prepared with large excess of free dimethylamine condensation
Methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides (1).The specific route that it is synthesized is as follows:
A large amount of sour gas HCl and SO is generated in being reacted in the preparation method2, environmental hazard is very big;Due to methyl esters (5)
Activity it is relatively small, therefore react with free dimethylamine and to need than relatively severe condition, unsuitable industrial production;Dimethylamine
The significantly excessive i.e. increase material loss that feeds intake, and increase the harm to environment.
Synthetic route disclosed in US2006/0084806 is with 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyrrole
Pyridine -3- acetic acid (2) is raw material, and DCM is solvent, and phosphorus oxychloride is acylating reagent, and corresponding acyl chlorides (3) is obtained through acylation reaction,
Then N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl are prepared with free dimethylamine condensation
Amine (1).The specific route that it is synthesized is as follows:
POCl in the preparation method3With high poison, a large amount of sour gas HCl and phosphorus-containing wastewater, environment are generated in reaction
Harm is big;The significantly excessive i.e. increase material loss that feeds intake of dimethylamine, and increase the harm to environment.
In short, above-mentioned all methods exist, reaction step length, severe reaction conditions, complicated for operation, reaction time is long, at
The deficiencies of this height, environmental pollution are seriously, industrialized production drawback is apparent;Serious offense has been used in especially all of above method
The free dimethylamine of amount, on the one hand causes material loss big, and cost increases, on the other hand again since excessive free dimethylamine is difficult
With recycling, becomes nitrogenous effluent, aggravated environmental pollution.
Therefore, the present invention in view of the good social benefit of current zolpidem and prepares N, N, 6- trimethyls -2- (4- methyl
Phenyl) imidazo [1,2-a] pyridine -3- acetamides reaction yield, commercial production conditions and environmental protection policy, provide one kind
Step that can be controllable, safe and environment-friendly prepares a kind of N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -
The effective ways of 3- acetamides.
Invention content
The purpose of the present invention is overcoming the above-mentioned prior art, provide it is a kind of can overcome existing synthetic route compared with
Long, dimethylamine wastes big, of high cost, production safety hidden danger, the big disadvantage of environmental hazard and controllable, safe and environment-friendly N, N, 6-
The preparation method of trimethyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides.
To achieve the goals above, N of the invention, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyrrole
The preparation method of pyridine -3- acetamides is as follows:
Under the action of condensing agent by 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acids (2) with
Dimethylamine salt carries out amidation process, obtains N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- second
Amide (1), reaction equation is as follows:
Preferably, the condensing agent is one or more in DCC, EDCI, DIC, TCT.
Preferably, the solvent of the amidation process is dichloromethane, dichloroethanes, tetrahydrofuran, ethyl acetate, first
Benzene, dioxane, acetone, n,N-Dimethylformamide, n,N-dimethylacetamide, C5~C7Linear paraffin or cycloalkane, second
One or more of glycol diethyl ether, formaldehyde contracting dimethyl ether, ether, methyl tertiary butyl ether(MTBE).
Preferably, the condensing agent and 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acid
Molar feed ratio is 0.5~5.0, the dimethylamine salt and described 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a]
The molar feed ratio of pyridine-3-acetic acid is 0.5~2.0.
Preferably, the condensing agent and 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acid
Molar feed ratio is 1.0~2.0, the dimethylamine salt and described 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a]
The molar feed ratio of pyridine-3-acetic acid is 0.95~1.1.
Preferably, the reaction temperature is -10~180 DEG C.
Preferably, the reaction temperature is 60~100 DEG C.
Preferably, the reaction time is 0.5~10h.
Preferably, the reaction time is 3~5h.
Preferably, the dimethylamine salt is dimethylamine hydrochloride, dimethylamine hydrobromate, diformazan amine phosphate, diformazan
It is one or more in amine sulfate.
N, the N of the present invention are used, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides
Preparation method, this method reaction condition is mild, it is easy to operate, convenient for purifying, high income, environmentally friendly, be suitble to industrialize
Production.
The present invention is a kind of efficient, stable, cleaner preparation method by facts have proved, thus it is speculated that its is possible
Reaction mechanism is following (by taking compound (2) and dimethylamine hydrochloride reacting in the presence of DCC as an example):
6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acid compounds (2) convert under DCC effects
Viability intermediate (6), (6) can seize the HCl in dimethylamine hydrochloride molecule and be converted to more active intermediate (7) and generate
Free dimethylamine, (7) are unstable can be rapidly converted to highly active acyl chlorides (3), and (3) are carried out with free dimethylamine again
Target product zolpidem (1) is smoothly made in amidation process.
Beneficial effects of the present invention are as follows:
The zolpidem of high-purity is made as raw material, a step in the dimethylamine salt for directly using market cheap and easy to get in high yield
(1);The inventory of dimethylamine salt has saved raw material close to theoretical amount, reduces cost, avoids environmental pollution;In reaction not
The sour gas of any hostile environment is released, is environmentally friendly preparation method;Reaction step is short, easy to operate, technique is steady
It is fixed, safely controllable;The unique by-product DCU generated in reaction does not dissolve in sour water, is dissolved in sour water using product zolpidem (1)
Feature is fully removed and is recycled, and the DCU purity of recycling reaches 99%;Do not generated in reaction noxious acidic " exhaust gas ",
Nitrogenous " waste water " few, unique " useless solid " DCU can be fully recycled, and cleanly production may be implemented.
Specific implementation mode
In order to more clearly describe the technology contents of the present invention, carried out with reference to specific embodiment further
Description.
The present invention provides N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides
Preparation method is as follows:
Under the action of condensing agent by 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acids (2) with
Dimethylamine salt carries out amidation process, obtains N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- second
Amide (1), reaction equation is as follows:
Wherein the condensing agent is DCC (dicyclohexylcarbodiimide), EDCI (1- (3- dimethylamino-propyls) -3- second
Base carbodiimide), DIC (diisopropylcarbodiimide), one or more of TCT (trichloro-triazine) share, from cost angle
Degree considers preferred DCC;The solvent of the amidation process is dichloromethane, dichloroethanes, tetrahydrofuran, ethyl acetate, first
Benzene, dioxane, acetone, n,N-Dimethylformamide, n,N-dimethylacetamide, C5~C7Linear paraffin or cycloalkane, second
One or more of glycol diethyl ether, formaldehyde contracting dimethyl ether, ether, methyl tertiary butyl ether(MTBE);The dimethylamine salt is diformazan
One or more in amine hydrochlorate, dimethylamine hydrobromate, diformazan amine phosphate, dimethylamine sulfate, dimethylamine salt can be with
In-situ preparation during market is bought or reacted.
In a kind of embodiment provided by the invention, the molar feed ratio of the condensing agent and compound (2) is 0.5
~5.0, the molar feed ratio of the dimethylamine salt and the compound (2) is 0.5~2.0;Preferably, the condensation
The molar feed ratio of agent and compound (2) is 1.0~2.0, and the dimethylamine salt and the compound (2) mole feed intake
Than being 0.95~1.1.
In a kind of embodiment provided by the invention, the reaction temperature is -10~180 DEG C;Preferably, described
Reaction temperature is 60~100 DEG C.
In a kind of embodiment provided by the invention, the reaction time is 0.5~10h;Preferably, described anti-
It is 3~5h between seasonable.
The preparation method only single step reaction of compound zolpidem (1) of the present invention, avoids that synthetic route is longer, makes
With high poison reagent, the shortcomings of cost is higher, environmental pollution is big.The present invention new method directly with market it is cheap and easy to get, property is steady
Fixed dimethylamine salt is raw material, directly exists in condensing agent with compound (2) and generates target product zolpidem (1) in next step, instead
Excessive many free dimethylamine are not needed in answering, do not generate any sour gas harmful to environment, dimethylamine salt dosage
It is small, be nearly free from that nitrogenous effluent, environment are more friendly, " useless solid " can fully recycle while avoid the prior art
In the triethylamine with penetrating odor, generally speaking that uses mostly, new method reaction condition is mild, reaction step is short, environment
Close friend, high income, high, at low cost, the suitable industrialized production of safety coefficient.
In order to make it easy to understand, the present invention will be described in detail by specific implementation mode below, need to refer in particular to
Go out, these descriptions are only exemplary description, and are not meant to limit the scope of the invention.In addition the present invention quotes
Open source literature is that their entire contents are included in be referred to herein in order to more clearly describe the present invention.
Embodiment 1
By the DMA of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acid (2),
6.40g dimethylamine hydrochlorides and 29.47g DCC are successively added in 500ml reaction bulbs, and stirring is warming up to 90~100 DEG C, heat preservation
3h stops reaction.It is recovered under reduced pressure solvent, 200ml water is added, with 6N hydrochloric acid tune pH=0.5~1,30min is stirred under room temperature, it is multiple
After survey pH is unchanged, a large amount of faint yellow solids are precipitated in filtering, filtrate liquid caustic soda tune pH=9~10, filter, and drying obtains yellowish
Color solid 20.96g (HPLC:99.2%), yield 95.6%.
Embodiment 2
By the dichloromethane of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- second
Sour (2), 5.79g dimethylamine hydrochlorides and 29.47g DCC are successively added in 500ml reaction bulbs, and stirring is warming up to reflux, are returned
8h is flowed, reaction is stopped.Post-processing obtains faint yellow solid 20.35g (HPLC with embodiment 1:99.0%), yield 92.8%.
Embodiment 3
By 1, the 2- dichloroethanes of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -
3- acetic acid (2), 9.83g dimethylamine hydrobromate and 27.41g EDCI are successively added in 500ml reaction bulbs, and stirring is warming up to
Reflux, flow back 5h, stops reaction.Post-processing obtains faint yellow solid 20.85g (HPLC with embodiment 1:99.1%), yield is
95.1%.
Embodiment 4
By the tetrahydrofuran of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- second
Sour (2), 6.30g dimethylamine sulfate and 29.47g DCC are successively added in 500ml reaction bulbs, and stirring is warming up to reflux, are protected
Temperature reaction 6h, stops reaction.Post-processing obtains faint yellow solid 19.86g (HPLC with embodiment 1:99.0%), yield is
90.6%.
Embodiment 5
By the toluene of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acid
(2), 6.10g diformazans amine phosphate and 13.10g TCT are successively added in 500ml reaction bulbs, and stirring is warming up to 90~100 DEG C,
5h is kept the temperature, reaction is stopped.Post-processing obtains faint yellow solid 20.53g (HPLC with embodiment 1:98.9%), yield is
93.6%.
Embodiment 6
By the dioxane of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- second
Sour (2), 6.07g dimethylamine hydrochlorides and 9.05g DIC are successively added in 500ml reaction bulbs, and stirring is warming up to reflux, are flowed back
10h stops reaction.Post-processing obtains faint yellow solid 18.66g (HPLC with embodiment 1:99.2%), yield 85.1%.
Embodiment 7
By the acetone of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acid
(2), dimethylamine hydrobromate (8.45g, 0.067mol, 0.95eq) and 21.98g DCC are successively added in 500ml reaction bulbs,
Stirring is warming up to reflux, and flow back 5h, stops reaction.Post-processing obtains faint yellow solid 19.56g (HPLC with embodiment 1:
98.8%), yield 89.2%.
Embodiment 8
By DMF, 20.00g compound 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- second of 200ml
Sour (2), 9.83g dimethylamine hydrobromate and 27.41g EDCI are successively added in 500ml reaction bulbs, and stirring is warming up to 70~
80 DEG C, insulation reaction 5h, stop reaction.Post-processing obtains faint yellow solid 20.50g (HPLC with embodiment 1:99.2%) it, receives
Rate is 93.5%.
Embodiment 9
By the methyl tertiary butyl ether(MTBE) of 200ml, 20.00g 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -
3- acetic acid (2), 6.07g dimethylamine hydrochlorides and 27.41g EDCI are successively added in 500ml reaction bulbs, and stirring is warming up to back
Stream, flow back 5h, stops reaction.Post-processing obtains faint yellow solid 20.28g (HPLC with embodiment 1:99.1%), yield is
92.5%.
The above-mentioned technical proposal for using the present invention, has the beneficial effect that:
The zolpidem of high-purity is made as raw material, a step in the dimethylamine salt for directly using market cheap and easy to get in high yield
(1);The inventory of dimethylamine salt has saved raw material close to theoretical amount, reduces cost, avoids environmental pollution;In reaction not
The sour gas of any hostile environment is released, is environmentally friendly preparation method;Reaction step is short, easy to operate, technique is steady
It is fixed, safely controllable;The unique by-product DCU generated in reaction does not dissolve in sour water, is dissolved in sour water using product zolpidem (1)
Feature is fully removed and is recycled, and the DCU purity of recycling reaches 99%;Do not generated in reaction noxious acidic " exhaust gas ",
Nitrogenous " waste water " few, unique " useless solid " DCU can be fully recycled, and cleanly production may be implemented.
In this description, the present invention is described with reference to its specific embodiment.But it is clear that can still make
Various modifications and alterations are without departing from the spirit and scope of the invention.Therefore, specification should be considered as illustrative rather than limit
Property processed.
Claims (8)
1. a kind of N, N, the preparation method of 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides,
It is characterized in that, the preparation method includes step:
By 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine-3-acetic acids (2) and diformazan under the action of condensing agent
Amine salt carries out amidation process, obtains N, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetamides
(1), reaction equation is as follows:
The dimethylamine salt is in dimethylamine hydrochloride, dimethylamine hydrobromate, diformazan amine phosphate, dimethylamine sulfate
One or more, the condensing agent is one or more in DCC, EDCI, DIC, TCT.
2. N according to claim 1, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl
The preparation method of amine, which is characterized in that the solvent of the amidation process is dichloromethane, dichloroethanes, tetrahydrofuran, second
Acetoacetic ester, toluene, dioxane, acetone, n,N-Dimethylformamide, n,N-dimethylacetamide, C5~C7Linear paraffin or
One or more of cycloalkane, ethylene glycol diethyl ether, formaldehyde contracting dimethyl ether, ether, methyl tertiary butyl ether(MTBE).
3. N according to claim 1, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl
The preparation method of amine, which is characterized in that the condensing agent and 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -
The molar feed ratio of 3- acetic acid is 0.5~5.0, the dimethylamine salt and described 6- methyl -2- (4- aminomethyl phenyls) imidazoles
And the molar feed ratio of [1,2-a] pyridine-3-acetic acid is 0.5~2.0.
4. N according to claim 1, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl
The preparation method of amine, which is characterized in that the condensing agent and 6- methyl -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -
The molar feed ratio of 3- acetic acid is 1.0~2.0, the dimethylamine salt and described 6- methyl -2- (4- aminomethyl phenyls) imidazoles
And the molar feed ratio of [1,2-a] pyridine-3-acetic acid is 0.95~1.1.
5. N according to claim 1, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl
The preparation method of amine (1), which is characterized in that the reaction temperature is -10~180 DEG C.
6. N according to claim 1, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl
The preparation method of amine (1), which is characterized in that the reaction temperature is 60~100 DEG C.
7. N according to claim 1, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl
The preparation method of amine (1), which is characterized in that the reaction time is 0.5~10h.
8. N according to claim 1, N, 6- trimethyls -2- (4- aminomethyl phenyls) imidazo [1,2-a] pyridine -3- acetyl
The preparation method of amine (1), which is characterized in that the reaction time is 3~5h.
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