CN105061293A - Synthesis method of gliclazide intermediate (amino azacyclo-hydrochloride) - Google Patents
Synthesis method of gliclazide intermediate (amino azacyclo-hydrochloride) Download PDFInfo
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- CN105061293A CN105061293A CN201510452783.1A CN201510452783A CN105061293A CN 105061293 A CN105061293 A CN 105061293A CN 201510452783 A CN201510452783 A CN 201510452783A CN 105061293 A CN105061293 A CN 105061293A
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- hydrochloride
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- 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 synthesis method of a gliclazide intermediate (amino azacyclo-hydrochloride). The method comprises the following steps: adding water, N-nitroso aza-cyclic compounds, and palladium/carbon into a reaction steel cylinder, introducing nitrogen gas into the steel cylinder to dispel the air, heating the steel cylinder to a temperature of 55 to 60 DEG C, introducing hydrogen gas into the reaction steel cylinder until the pressure reaches 1.5 MP, maintaining the pressure in a range of 1.0 to 1.5 MP, wherein when the pressure does not descend, the reactions are finished; cooling the reaction steel cylinder to a temperature lower than 15 DEG C, discharging hydrogen gas in the cylinder, replacing the hydrogen gas by nitrogen gas, filtering to remove palladium/carbon, saving the filtrate; adding liquid alkali and toluene into the filtrate, stirring, allowing the filtrate to stand still, removing the water in the lower layer, saving the upper toluene layer; adding hydrochloric acid into the toluene layer until the pH reaches 2-3, stirring, allowing the toluene layer stand still, removing the water layer, distilling the toluene layer until no water is left, adding anhydrous ethanol into the distillation residues, heating to dissolve the residues, cooling to dissolve out crystals, and filtering so as to obtain the gliclazide intermediate (amino azacyclo-hydrochloride). The provided method improves the yield and reduces the slag.
Description
Technical field
The invention belongs to pharmacy field, particularly relate to a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride.
Background technology
Gliclazide is s-generation sulfourea hypoglycemic agents, and effect is comparatively strong, and its mechanism optionally acts on beta Cell of islet, promotes insulin secretion.By insulin receptor mechanism of action, increase the activity of glycogen synthetase in bone, promote that muscle is to the utilization of glucose, and can hematoblastic gathering and adhesive power be reduced, contribute to preventing and treating diabetic microvascular complication.The synthesis of gliclazide intermediate aminoazaheterocycles hydrochloride adopted toluene to make reaction solvent in the past, adopt under anhydrous condition that zinc powder is anti-former, filtration, extraction, distillation, elutriation crystallization, filtration, drying and obtaining.Mainly there is yield low, the shortcomings such as solid waste amount is many.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, solves its yield low, the problem that solid waste amount is many, improves reaction yield, reduces reaction solid waste output, is convenient to cleaner production.
For solving the problems of the technologies described above, the invention provides a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, comprising the following steps:
(1) in reaction steel cylinder, add water, N-nitroso-group nitrogen heterocyclic, palladium/charcoal, after logical nitrogen replacement air, be slowly warming up to 55-60 DEG C, logical hydrogen is 1.5MP to reaction steel cylinder pressure, at 55-60 DEG C of temperature, maintains pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates;
(2) reaction steel cylinder is cooled to less than 15 DEG C, and slowly gets rid of hydrogen in bottle, and use nitrogen replacement hydrogen, then cross and filter palladium/charcoal, retain filtrate;
(3) in described filtrate, add liquid caustic soda, toluene, then stir 30 minutes, leave standstill 30 minutes, point sub-cloud water, retain upper toluene layer;
(4) in toluene layer, dripping hydrochloric acid to PH is 2-3, stirs 30 minutes, leaves standstill 30 minutes, branch vibration layer, after described toluene layer is distilled to and does, adds dehydrated alcohol in distillation residuum, after heating for dissolving, cooling folding is brilliant, filters to obtain gliclazide intermediate aminoazaheterocycles hydrochloride.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, described in described step (1), the mol ratio of water and N-nitroso-group nitrogen heterocyclic is 15:1.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, described in described step (1), the number of times of logical nitrogen replacement air is 3 times.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, the consumption of palladium/charcoal described in described step (1) is the 4.5-5.5% of the weight of the consumption of N-nitroso-group nitrogen heterocyclic.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, it is 3 times with the number of times of nitrogen replacement hydrogen described in described step (2).
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, described in described step (3), the concentrations by weight of liquid caustic soda is 30%.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, the volume of liquid caustic soda described in described step (3) is 3 times amount of described filtrate volume.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, the volume of toluene described in described step (3) is 7 times amount of described filtrate volume.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, described in described step (4), the weight percent of hydrochloric acid is 30%.
As a kind of preferred version of the synthetic method of a kind of gliclazide intermediate aminoazaheterocycles hydrochloride of the present invention, the volume of dehydrated alcohol described in described step (4) is 15 times amount of the volume of distillation residuum.
The invention discloses a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, make yield bring up to about 83.75% from original 75.28%, post-reaction treatment waste residue obviously reduces, and is conducive to cleaner production.
Embodiment
The invention provides a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, comprise the following steps:
(1) in reaction steel cylinder, add water, N-nitroso-group nitrogen heterocyclic, palladium/charcoal, after logical nitrogen replacement air, be slowly warming up to 55-60 DEG C, logical hydrogen is 1.5MP to reaction steel cylinder pressure, at 55-60 DEG C of temperature, maintains pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates;
(2) reaction steel cylinder is cooled to less than 15 DEG C, and slowly gets rid of hydrogen in bottle, and use nitrogen replacement hydrogen, then cross and filter palladium/charcoal, retain filtrate;
(3) in described filtrate, add liquid caustic soda, toluene, then stir 30 minutes, leave standstill 30 minutes, point sub-cloud water, retain upper toluene layer;
(4) in toluene layer, dripping hydrochloric acid to PH is 2-3, stirs 30 minutes, leaves standstill 30 minutes, branch vibration layer, after described toluene layer is distilled to and does, adds dehydrated alcohol in distillation residuum, after heating for dissolving, cooling folding is brilliant, filters to obtain gliclazide intermediate aminoazaheterocycles hydrochloride.
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, and below in conjunction with embodiment, the present invention is further detailed explanation.
A synthetic method for gliclazide intermediate aminoazaheterocycles hydrochloride, comprising:
Step one: add water, N-nitroso-group nitrogen heterocyclic, palladium/charcoal in reaction steel cylinder, after logical nitrogen replacement air, is slowly warming up to 55-60 DEG C, and logical hydrogen is 1.5MP to reaction steel cylinder pressure,
At 55-60 DEG C of temperature, maintain pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates;
In one embodiment, this step can specific as followsly perform: in reaction steel cylinder, add water, N-nitroso-group nitrogen heterocyclic, palladium/charcoal, the mol ratio of wherein said water and N-nitroso-group nitrogen heterocyclic is 15:1, the consumption of described palladium/charcoal is the 4.5-5.5% of the weight of the consumption of N-nitroso-group nitrogen heterocyclic, then after logical nitrogen replacement air 3 times, slowly be warming up to 55-60 DEG C, logical hydrogen is 1.5MP to reaction steel cylinder pressure, at 55-60 DEG C of temperature, maintain pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates.
Step 2: reaction steel cylinder is cooled to less than 15 DEG C, and slowly get rid of hydrogen in bottle, and use nitrogen replacement hydrogen, then cross and filter palladium/charcoal, retain filtrate;
In one embodiment, this step can specific as followsly perform: reaction steel cylinder is cooled to less than 15 DEG C, and slowly gets rid of hydrogen in bottle, and with nitrogen hydrogen exchange 3 times, then crosses and filter palladium/charcoal, retention filtrate.
Step 3: add liquid caustic soda, toluene in described filtrate, then stirs 30 minutes, leaves standstill 30 minutes, and point sub-cloud water retains upper toluene layer; With
In one embodiment, this step can specific as followsly perform: in described filtrate, add liquid caustic soda, toluene, wherein, the concentrations by weight of described liquid caustic soda is 30%, and the volume of described liquid caustic soda is 3 times amount of described filtrate volume, and the volume of described toluene is 7 times amount of described filtrate volume, then stir 30 minutes, leave standstill 30 minutes, point sub-cloud water, retain upper toluene layer.
Step 4: dripping hydrochloric acid to PH in toluene layer is 2-3, stirs 30 minutes, leaves standstill 30 minutes, branch vibration layer, after described toluene layer is distilled to and does, adds dehydrated alcohol in distillation residuum, after heating for dissolving, cooling folding is brilliant, filters to obtain gliclazide intermediate aminoazaheterocycles hydrochloride.
In one embodiment, this step can specific as followsly perform: in toluene layer, dripping hydrochloric acid to PH is 2-3, stirs 30 minutes, leave standstill 30 minutes, wherein, the weight percent of described hydrochloric acid is 30%, branch vibration layer, after described toluene layer is distilled to and does, in distillation residuum, add dehydrated alcohol, the volume of described dehydrated alcohol is 15 times amount of the volume of distillation residuum, after heating for dissolving, cooling folding is brilliant, filters to obtain gliclazide intermediate aminoazaheterocycles hydrochloride.
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, further illustrate technical scheme of the present invention below in conjunction with embodiment.But the invention is not restricted to listed embodiment, also should be included in other any known changes in interest field of the presently claimed invention.
First, alleged herein " embodiment " or " embodiment " refers to special characteristic, structure or the characteristic that can be contained at least one implementation of the present invention.Different local in this manual " in one embodiment " occurred not all refers to same embodiment, neither be independent or optionally mutually exclusive with other embodiments embodiment.
Embodiment one
Quantitative water is added in reaction steel cylinder, 4.5% palladium/the charcoal of N-nitroso-group nitrogen heterocyclic and N-nitroso-group azepine circular rector, after logical nitrogen replacement air 3 times, slowly be warming up to 55 DEG C, logical hydrogen is 1.5MP to reaction steel cylinder pressure, at this temperature, maintain pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates, below cooling reaction flask to 15 DEG C, and slowly get rid of hydrogen in bottle, and with nitrogen replacement 3 times, complete, cross and filter palladium/charcoal, filtrate adds the liquid caustic soda of 30%, quantitative toluene, stir 30 minutes, leave standstill 30 minutes, divide sub-cloud water, in toluene layer, dripping 30% hydrochloric acid to PH is 2-3, stir 30 minutes, leave standstill 30 minutes, after water layer is distilled to and does, add dehydrated alcohol, after heating for dissolving, cooling folding is brilliant, filter to obtain gliclazide intermediate aminoazaheterocycles hydrochloride, yield 83.05%.
Embodiment two
Quantitative water is added in reaction steel cylinder, 5% palladium/the charcoal of N-nitroso-group nitrogen heterocyclic and N-nitroso-group azepine circular rector, after logical nitrogen replacement air 3 times, slowly be warming up to 57 DEG C, logical hydrogen is 1.5MP to reaction steel cylinder pressure, at this temperature, maintain pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates, below cooling reaction flask to 15 DEG C, and slowly get rid of hydrogen in bottle, and with nitrogen replacement 3 times, complete, cross and filter palladium/charcoal, filtrate adds the liquid caustic soda of 30%, quantitative toluene, stir 30 minutes, leave standstill 30 minutes, divide sub-cloud water, in toluene layer, dripping 30% hydrochloric acid to PH is 2-3, stir 30 minutes, leave standstill 30 minutes, after water layer is distilled to and does, add dehydrated alcohol, after heating for dissolving, cooling folding is brilliant, filter to obtain gliclazide intermediate aminoazaheterocycles hydrochloride, yield 83.25%.
Embodiment three
Quantitative water is added in reaction steel cylinder, 5.5% palladium/the charcoal of N-nitroso-group nitrogen heterocyclic and N-nitroso-group azepine circular rector, after logical nitrogen replacement air 3 times, slowly be warming up to 60 DEG C, logical hydrogen is 1.5MP to reaction steel cylinder pressure, at this temperature, maintain pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates, below cooling reaction flask to 15 DEG C, and slowly get rid of hydrogen in bottle, and with nitrogen replacement 3 times, complete, cross and filter palladium/charcoal, filtrate adds the liquid caustic soda of 30%, quantitative toluene, stir 30 minutes, leave standstill 30 minutes, divide sub-cloud water, in toluene layer, dripping 30% hydrochloric acid to PH is 2-3, stir 30 minutes, leave standstill 30 minutes, after water layer is distilled to and does, add dehydrated alcohol, after heating for dissolving, cooling folding is brilliant, filter to obtain gliclazide intermediate aminoazaheterocycles hydrochloride, yield 86.75%.
The gliclazide intermediate aminoazaheterocycles hydrochloride quality that embodiment one to three obtains meets inner controlling standard of enterprise, and the finished product gliclazide meets Chinese Pharmacopoeia 2010 editions standards
In sum, the invention discloses a kind of synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride, its remarkable advantage is:
1, present method improves gliclazide intermediate reaction yield 8.47%;
2, The method reduces the solid waste in production process, be conducive to cleaner production;
3, present approach reduces gliclazide product cost.
It should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (10)
1. a synthetic method for gliclazide intermediate aminoazaheterocycles hydrochloride, it comprises:
(1) in reaction steel cylinder, add water, N-nitroso-group nitrogen heterocyclic, palladium/charcoal, after logical nitrogen replacement air, be slowly warming up to 55-60 DEG C, logical hydrogen is 1.5MP to reaction steel cylinder pressure, at 55-60 DEG C of temperature, maintains pressure at 1.0-1.5MP, when pressure does not fall, reaction terminates;
(2) reaction steel cylinder is cooled to less than 15 DEG C, and slowly gets rid of hydrogen in bottle, and use nitrogen replacement hydrogen, then cross and filter palladium/charcoal, retain filtrate;
(3) in described filtrate, add liquid caustic soda, toluene, then stir 30 minutes, leave standstill 30 minutes, point sub-cloud water, retain upper toluene layer;
(4) in toluene layer, dripping hydrochloric acid to PH is 2-3, stirs 30 minutes, leaves standstill 30 minutes, branch vibration layer, after described toluene layer is distilled to and does, adds dehydrated alcohol in distillation residuum, after heating for dissolving, cooling folding is brilliant, filters to obtain gliclazide intermediate aminoazaheterocycles hydrochloride.
2. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: described in described step (1), the mol ratio of water and N-nitroso-group nitrogen heterocyclic is 15:1.
3. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: described in described step (1), the number of times of logical nitrogen replacement air is 3 times.
4. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: the consumption of palladium/charcoal described in described step (1) is the 4.5-5.5% of the weight of the consumption of N-nitroso-group nitrogen heterocyclic.
5. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: be 3 times with the number of times of nitrogen replacement hydrogen described in described step (2).
6. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: described in described step (3), the concentrations by weight of liquid caustic soda is 30%.
7. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: the volume of liquid caustic soda described in described step (3) is 3 times amount of described filtrate volume.
8. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: the volume of toluene described in described step (3) is 7 times amount of described filtrate volume.
9. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: described in described step (4), the weight percent of hydrochloric acid is 30%.
10. the synthetic method of gliclazide intermediate aminoazaheterocycles hydrochloride as claimed in claim 1, is characterized in that: the volume of dehydrated alcohol described in described step (4) is 15 times amount of the volume of distillation residuum.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372568A (en) * | 2019-08-22 | 2019-10-25 | 山东海佑福瑞达制药有限公司 | A kind of crystallization and preparation method thereof of gliclazide intermediate |
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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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- 2015-07-28 CN CN201510452783.1A patent/CN105061293B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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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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| 杨锦宗: "《工业有机合成基础》", 31 December 1998 * |
| 梅光明: "格列齐特的合成", 《浙江大学硕士学位论文》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372568A (en) * | 2019-08-22 | 2019-10-25 | 山东海佑福瑞达制药有限公司 | A kind of crystallization and preparation method thereof of gliclazide intermediate |
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