CN105061293B - A kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride - Google Patents
A kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride Download PDFInfo
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- CN105061293B CN105061293B CN201510452783.1A CN201510452783A CN105061293B CN 105061293 B CN105061293 B CN 105061293B CN 201510452783 A CN201510452783 A CN 201510452783A CN 105061293 B CN105061293 B CN 105061293B
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- aminoazaheterocycles
- hydrochloride
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- gliclazide
- hydrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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Abstract
The invention discloses a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, it includes：Reaction steel cylinder in add water,
Description
Technical field
The invention belongs to pharmaceutical field, more particularly to a kind of synthesis side of gliclazide intermediate aminoazaheterocycles hydrochloride
Method.
Background technology
Gliclazide is second generation sulfonylureas hypoglycemic agent, acts on stronger, its mechanism is that to be selectively applied to pancreas islet β thin
Born of the same parents, promote insulin secretion.By insulin receptor mechanism of action, increase the activity of glycogen synthetase in bone, promote muscle
Utilization to glucose, and hematoblastic aggregation and adhesion can be reduced, help to prevent and treat diabetic microvascular complication.Ge Lieqi
Made before special intermediate aminoazaheterocycles hydrochloride synthesis using toluene under reaction dissolvent, anhydrous condition using the anti-former, mistake of zinc powder
Filter, extraction, distillation, elutriation crystallize, filter, dry and obtain.It is primarily present yield low, the shortcomings of solid waste amount is more.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of synthesis of gliclazide intermediate aminoazaheterocycles hydrochloride
Method, it is low to solve its yield, the problem of solid waste amount is more, improves reaction yield, reduction reaction solid waste output, is easy to clean manufacturing.
In order to solve the above technical problems, the present invention provides a kind of synthesis of gliclazide intermediate aminoazaheterocycles hydrochloride
Method, comprises the following steps：
(1) reaction steel cylinder in add water,Palladium/charcoal, leads to after nitrogen displacement air, slowly
55-60 DEG C is warming up to, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted, at a temperature of 55-60 DEG C, maintains pressure in 1.0-
1.5MP, when pressure does not drop, reaction terminates；
(2) reaction steel cylinder is cooled to less than 15 DEG C, and slowly excludes hydrogen in bottle, and use nitrogen displacement hydrogen, then
Palladium/charcoal is filtered to remove, filtrate is retained；
(3) liquid caustic soda, toluene are added in the filtrate, is then stirred 30 minutes, 30 minutes are stood, point sub-cloud water is stayed
Deposit upper toluene layer；
(4) it is 2-3 that hydrochloric acid is added dropwise in toluene layer to PH, stirs 30 minutes, stands 30 minutes, branch vibration layer, the first
Benzene layer is distilled to after doing, and after adding absolute ethyl alcohol, heating for dissolving in distillation residue, cooling crystallization filters to obtain gliclazide
Intermediate
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, water described in the step (1) andMol ratio be 15：1.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the number of times that nitrogen displacement air is led to described in the step (1) is 3 times.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the consumption of palladium/charcoal is described in the step (1)Consumption weight 4.5-
5.5%.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the number of times that nitrogen displacement hydrogen is used described in the step (2) is 3 times.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the concentrations by weight of liquid caustic soda described in the step (3) is 30%.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the volume of liquid caustic soda described in the step (3) is 3 times of amounts of the filtrate volume.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the volume of toluene described in the step (3) is 7 times of amounts of the filtrate volume.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the percentage by weight of hydrochloric acid described in the step (4) is 30%.
It is preferred as a kind of one kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention
Scheme, the volume of absolute ethyl alcohol described in the step (4) is measured to distill 15 times of the volume of residue.
The invention discloses a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, make yield from original
75.28% bring up to 83.75% or so, post-reaction treatment waste residue is significantly reduced, and is conducive to clean manufacturing.
Embodiment
The present invention provides a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, comprises the following steps：
(1) reaction steel cylinder in add water,Palladium/charcoal, leads to after nitrogen displacement air, slowly
55-60 DEG C is warming up to, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted, at a temperature of 55-60 DEG C, maintains pressure in 1.0-
1.5MP, when pressure does not drop, reaction terminates；
(2) reaction steel cylinder is cooled to less than 15 DEG C, and slowly excludes hydrogen in bottle, and use nitrogen displacement hydrogen, then
Palladium/charcoal is filtered to remove, filtrate is retained；
(3) liquid caustic soda, toluene are added in the filtrate, is then stirred 30 minutes, 30 minutes are stood, point sub-cloud water is stayed
Deposit upper toluene layer；
(4) it is 2-3 that hydrochloric acid is added dropwise in toluene layer to PH, stirs 30 minutes, stands 30 minutes, branch vibration layer, the first
Benzene layer is distilled to after doing, and after adding absolute ethyl alcohol, heating for dissolving in distillation residue, cooling crystallization filters to obtain gliclazide
Intermediate
In order to facilitate the understanding of the purposes, features and advantages of the present invention, with reference to embodiment
The present invention is further detailed explanation.
A kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, including：
Step one：Reaction steel cylinder in add water,Palladium/charcoal, leads to after nitrogen displacement air,
55-60 DEG C is slowly warming up to, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted, at a temperature of 55-60 DEG C, maintains pressure in 1.0-
1.5MP, when pressure does not drop, reaction terminates；
In one embodiment, the step can be performed with specific as follows：Reaction steel cylinder in add water,Palladium/charcoal, wherein the water andMol ratio be 15：1, it is described
The consumption of palladium/charcoal isConsumption weight 4.5-5.5%, then lead to nitrogen displacement air 3 times
Afterwards, 55-60 DEG C is slowly warming up to, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted, at a temperature of 55-60 DEG C, maintains pressure to exist
1.0-1.5MP, when pressure does not drop, reaction terminates.
Step 2：Reaction steel cylinder is cooled to less than 15 DEG C, and slowly hydrogen in exclusion bottle, and uses nitrogen displacement hydrogen,
Then palladium/charcoal is filtered to remove, filtrate is retained；
In one embodiment, the step can be performed with specific as follows：Reaction steel cylinder is cooled to less than 15 DEG C, and slowly
Hydrogen in bottle is excluded, and is replaced 3 times with nitrogen hydrogen, palladium/charcoal is then filtered to remove, retains filtrate.
Step 3：Liquid caustic soda, toluene are added in the filtrate, is then stirred 30 minutes, 30 minutes are stood, point sub-cloud
Water, retains upper toluene layer；With
In one embodiment, the step can be performed with specific as follows：Liquid caustic soda, toluene are added in the filtrate, wherein,
The concentrations by weight of the liquid caustic soda is 30%, and the volume of the liquid caustic soda is 3 times of amounts of the filtrate volume, the volume of the toluene
For 7 times of amounts of the filtrate volume, then stir 30 minutes, stand 30 minutes, point sub-cloud water retains upper toluene layer.
Step 4：It is 2-3 that hydrochloric acid is added dropwise in toluene layer to PH, stirs 30 minutes, stands 30 minutes, branch vibration layer, institute
State toluene layer to distill to after doing, after adding absolute ethyl alcohol, heating for dissolving in distillation residue, cooling crystallization filters get Ge Lie
Neat spy's intermediate aminoazaheterocycles hydrochloride.
In one embodiment, the step can be performed with specific as follows：It is 2-3 that hydrochloric acid is added dropwise in toluene layer to PH, is stirred
Mix 30 minutes, stand 30 minutes, wherein, the percentage by weight of the hydrochloric acid is 30%, branch vibration layer, the toluene layer distill to
After dry, absolute ethyl alcohol is added in distillation residue, the volume of the absolute ethyl alcohol is measured to distill 15 times of the volume of residue,
After heating for dissolving, cooling crystallization filters to obtain gliclazide intermediate
In order to facilitate the understanding of the purposes, features and advantages of the present invention, it is further with reference to embodiment
Illustrate technical scheme.But the invention is not restricted to listed embodiment, should also be included in of the presently claimed invention
Other any known changes in interest field.
First, " one embodiment " or " embodiment " referred to herein refers to may be included at least one realization side of the invention
Special characteristic, structure or characteristic in formula." in one embodiment " that different places occur in this manual not refers both to
Same embodiment, nor the single or selective embodiment mutually exclusive with other embodiment.
Embodiment one
Reaction steel cylinder in add quantitative water,AndAmount
4.5% palladium/charcoal, lead to after nitrogen displacement air 3 times, be slowly warming up to 55 DEG C, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted,
At this temperature, maintain pressure in 1.0-1.5MP, when pressure does not drop, reaction terminates, cool down reaction bulb to less than 15 DEG C, and
It is slow to exclude hydrogen in bottle, and with nitrogen displacement 3 times, finish, be filtered to remove palladium/charcoal, the liquid caustic soda of filtrate addition 30% is quantitative
Toluene, is stirred 30 minutes, stands 30 minutes, point sub-cloud water, and it is 2-3 that 30% hydrochloric acid is added dropwise in toluene layer to PH, stirs 30
Minute, 30 minutes are stood, water layer is distilled to after doing, and is added after absolute ethyl alcohol, heating for dissolving, cooling crystallization, filters get Ge Lieqi
Special intermediateYield 83.05%.
Embodiment two
Reaction steel cylinder in add quantitative water,AndAmount
5% palladium/charcoal, lead to after nitrogen displacement air 3 times, be slowly warming up to 57 DEG C, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted,
At a temperature of this, maintain pressure in 1.0-1.5MP, when pressure does not drop, reaction terminates, cooling reaction bulb delays to less than 15 DEG C
It is slow to exclude hydrogen in bottle, and with nitrogen displacement 3 times, finish, be filtered to remove palladium/charcoal, the liquid caustic soda of filtrate addition 30%, quantitative first
Benzene, is stirred 30 minutes, stands 30 minutes, point sub-cloud water, and it is 2-3 that 30% hydrochloric acid is added dropwise in toluene layer to PH, stirs 30 points
Clock, stands 30 minutes, and water layer is distilled to after doing, and is added after absolute ethyl alcohol, heating for dissolving, cooling crystallization filters to obtain gliclazide
IntermediateYield 83.25%.
Embodiment three
Reaction steel cylinder in add quantitative water,AndAmount
5.5% palladium/charcoal, lead to after nitrogen displacement air 3 times, be slowly warming up to 60 DEG C, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted,
At this temperature, maintain pressure in 1.0-1.5MP, when pressure does not drop, reaction terminates, cool down reaction bulb to less than 15 DEG C, and
It is slow to exclude hydrogen in bottle, and with nitrogen displacement 3 times, finish, be filtered to remove palladium/charcoal, the liquid caustic soda of filtrate addition 30% is quantitative
Toluene, is stirred 30 minutes, stands 30 minutes, point sub-cloud water, and it is 2-3 that 30% hydrochloric acid is added dropwise in toluene layer to PH, stirs 30
Minute, 30 minutes are stood, water layer is distilled to after doing, and is added after absolute ethyl alcohol, heating for dissolving, cooling crystallization, filters get Ge Lieqi
Special intermediateYield 86.75%.
The gliclazide intermediate aminoazaheterocycles hydrochloride quality that embodiment one to three is obtained meets inner controlling standard of enterprise,
Final products gliclazide meets 2010 editions standards of Chinese Pharmacopoeia
In summary, the invention discloses a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, its
Remarkable advantage is：
1st, this method improves gliclazide intermediate reaction yield 8.47%；
2nd, The method reduces the solid waste in production process, clean manufacturing is conducive to；
3rd, present approach reduces gliclazide product cost.
It should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to preferable
The present invention is described in detail embodiment, it will be understood by those within the art that, can be to technology of the invention
Scheme is modified or equivalent substitution, and without departing from the spirit and scope of technical solution of the present invention, it all should cover in this hair
Among bright right.
Claims (10)
1. a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, it includes：
(1) reaction steel cylinder in add water,Palladium/charcoal, leads to after nitrogen displacement air, slowly heats up
To 55-60 DEG C, it is 1.5MP to lead to hydrogen to steel cylinder pressure is reacted, at a temperature of 55-60 DEG C, maintains pressure in 1.0-1.5MP, when
When pressure does not drop, reaction terminates；
(2) reaction steel cylinder is cooled to less than 15 DEG C, and slowly excludes hydrogen in bottle, and use nitrogen displacement hydrogen, then filtered
Palladium/charcoal is removed, filtrate is retained；
(3) liquid caustic soda, toluene are added in the filtrate, is then stirred 30 minutes, 30 minutes are stood, divided in sub-cloud water, retention
Layer toluene layer；
(4) it is 2-3 that hydrochloric acid is added dropwise in toluene layer to PH, stirs 30 minutes, stands 30 minutes, branch vibration layer, the toluene layer
Distillation is to after dry, after adding absolute ethyl alcohol, heating for dissolving in distillation residue, cooling crystallization, filter in the middle of gliclazide
Body
2. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
State water described in step (1) andMol ratio be 15：1.
3. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
State and lead to the number of times of nitrogen displacement air described in step (1) for 3 times.
4. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
Stating the consumption of palladium/charcoal described in step (1) isConsumption weight 4.5-5.5%.
5. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
State and the number of times of nitrogen displacement hydrogen is used described in step (2) for 3 times.
6. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
The concentrations by weight for stating liquid caustic soda described in step (3) is 30%.
7. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
State 3 times amounts of the volume of liquid caustic soda described in step (3) for the filtrate volume.
8. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
State 7 times amounts of the volume of toluene described in step (3) for the filtrate volume.
9. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：Institute
The percentage by weight for stating hydrochloric acid described in step (4) is 30%.
10. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, it is characterised in that：
The volume of absolute ethyl alcohol described in the step (4) is measured to distill 15 times of the volume of residue.
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Citations (3)
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|---|---|---|---|---|
| AR203750A1 (en) * | 1973-07-04 | 1975-10-15 | Science Union & Cie | PROCEDURE FOR THE PREPARATION OF N-ARYLSULFONIL N '- (AZA-3 BICYCLOALKYL) UREAS |
| CN102382034A (en) * | 2010-09-06 | 2012-03-21 | 山东方明药业股份有限公司 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN102584677A (en) * | 2012-02-07 | 2012-07-18 | 安徽金鼎医药有限公司 | Method for preparing gliclazide |
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2015
- 2015-07-28 CN CN201510452783.1A patent/CN105061293B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR203750A1 (en) * | 1973-07-04 | 1975-10-15 | Science Union & Cie | PROCEDURE FOR THE PREPARATION OF N-ARYLSULFONIL N '- (AZA-3 BICYCLOALKYL) UREAS |
| CN102382034A (en) * | 2010-09-06 | 2012-03-21 | 山东方明药业股份有限公司 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN102584677A (en) * | 2012-02-07 | 2012-07-18 | 安徽金鼎医药有限公司 | Method for preparing gliclazide |
Non-Patent Citations (1)
| Title |
|---|
| 格列齐特的合成;梅光明;《浙江大学硕士学位论文》;20060831;第16-17、26-27页 * |
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