CN107857795A - The preparation method of glycylglutamine impurity - Google Patents
The preparation method of glycylglutamine impurity Download PDFInfo
- Publication number
- CN107857795A CN107857795A CN201711138062.9A CN201711138062A CN107857795A CN 107857795 A CN107857795 A CN 107857795A CN 201711138062 A CN201711138062 A CN 201711138062A CN 107857795 A CN107857795 A CN 107857795A
- Authority
- CN
- China
- Prior art keywords
- glycyl
- preparation
- pht
- glycylglutamine
- glutamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation method of glycylglutamine impurity, belong to medical synthesis technical field.Described preparation method, is comprised the following steps that:(1) preparation of N Pht glycine;(2) preparation of N Pht glycyl chlorides;(3) preparation of N Pht glycyl glycyl L glutamine;(4) preparation of glycyl glycyl L glutamine.The invention provides a kind of preparation method of impurity glycyl glycyl L glutamine in glycylglutamine bulk drug, the highway route design is reasonable, it is simple to operate, reaction condition is gentle, raw material is easy to get, and up to more than 99%, the reference substance that can be studied as glycylglutamine impurity uses gained impurity purity, for the qualitative and quantitative analysis of impurity, there is positive effect to glycylglutamine bulk drug quality research.
Description
Technical field
The present invention relates to a kind of preparation method of glycylglutamine impurity, belong to medical synthesis technical field.
Background technology
Glycylglutamine is a kind of artificial synthesized dipeptides amino acid, is in the double peptide injections of amino acid
One of main component.Glycylglutamine is mainly used in providing glutamine, to promote the synthesis of protein, meanwhile, sweet ammonia
Acyl glutamine has certain protective effect to cardiovascular system, intestinal tract and immune system.
Glycyl glycyl-L-glutamine (compound 1), is the process contaminants of glycylglutamine, and structure is as follows
It is shown.The report on glycyl glycyl-L glutamine preparation methods is there is no at present.
Because in the production process of glycylglutamine, with glycylglutamine condensation reaction occurs for glycine,
So as to inevitably produce accessory substance glycyl glycyl-L-glutamine.Glycyl paddy can be used for the miscellaneous Quality Research
The qualitative and quantitative analysis of impurity in glutamine, to improving the quality standard of glycylglutamine, carrying out pharmacological toxicology research tool
There is positive effect.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide one kind to react glycyl paddy ammonia gentle, simple to operate
The preparation method of amide impurities, product purity is high, and the quality research of glycylglutamine finished product can be used for as reference substance,
Improve quality control.
The preparation method of glycylglutamine impurity of the present invention, reaction scheme are as follows
The preparation method of glycylglutamine impurity of the present invention, is comprised the following steps that:
(1) glycine (compound 2), phthalic anhydride and triethylamine are added in toluene, are heated to reflux 5~10h, then drop
Temperature, add concentrated hydrochloric acid and adjust pH value to 3~4, be down to room temperature, filter, obtain N-Pht- glycine (compound 3);
(2) N-Pht- glycine is added in toluene, adds thionyl chloride, heating reflux reaction, reaction is finished, is evaporated off
Solvent, using re crystallization from toluene, obtain N-Pht- glycyl chlorides (compound 4);
(3) toluene is added into sodium hydroxide solution, is cooled, adds glycyl-L-glutamine (compound 5), is added dropwise
The toluene solution of N-Pht- glycyl chlorides, while sodium hydroxide solution is added dropwise and maintains pH value 7~8;It is added dropwise, is stirred at room temperature
0.5~2h, stand, liquid separation, aqueous phase adjusts pH value to 2~3 with concentrated hydrochloric acid, continues 0.5~2h of stirring and crystallizing, filters, obtain N-
Pht- glycyl glycyl-L-glutamine (compound 6);
(4) N-Pht- glycyl glycyl-L-glutamine (compound 6) is suspended in methanol, in hydrazine hydrate, three second
Reacted under amine, the methanol solution of organic acid is then added dropwise, filtered, filter cake is washed with water, and methanol is added dropwise in filtrate, filters, obtains sweet
Aminoacyl glycyl-L-glutamine crude product, crude product obtain glycyl glycyl-L-glutamine (compound through water, refining methanol
1)。
Wherein:
The mol ratio of glycine, phthalic anhydride and triethylamine described in step (1) is 1:1~1.2:0.05~0.2.
The mol ratio of N-Pht- glycine and thionyl chloride described in step (2) is 1:1.2~2.
Reflux time described in step (2) is 3~7h.
In step (3), toluene is added into sodium hydroxide solution, is cooled, adds glycyl-L-glutamine, N- is added dropwise
The toluene solution of Pht- glycyl chlorides;Wherein, the mol ratio of glycyl-L-glutamine and sodium hydroxide in sodium hydroxide solution
For 1:1~1.5, temperature is -5~10 DEG C during the toluene solution of N-Pht- glycyl chlorides is added dropwise.
The mol ratio of N-Pht- glycyl glycyl-L-glutamine, hydrazine hydrate, triethylamine described in step (4) is 1:
1.05~1.1:1.1~1.2.
Being reacted under hydrazine hydrate, triethylamine described in step (4), reaction temperature be 40~50 DEG C, the reaction time be 4~
7h。
The methanol solution that organic acid is added dropwise in step (4) adjusts pH value to 5~6, and described organic acid is formic acid, acetic acid, lemon
One or more in lemon acid, tartaric acid, malic acid, maleic acid, fumaric acid, lactic acid, butanedioic acid or methanesulfonic acid.
Filter cake described in step (4) is washed with water, and methanol is added dropwise in filtrate, the dosage of water is the sweet ammonia of N-Pht- glycyl
Acyl-Glu feeds intake 1.5~3 times of quality, and the volume ratio of water and methanol is 1:2~6.
Crude product described in step (4) is specially through water, refining methanol:Crude product is suspended in water, rising temperature for dissolving, through activity
After carbon decoloring, methanol is added dropwise, filters;The quality of described water is 2~3 times of crude product quality, and the volume ratio of water and methanol is 1:2
~6.
Compared with prior art, the invention has the advantages that:
The invention provides a kind of system of impurity glycyl glycyl-L-glutamine in glycylglutamine bulk drug
Preparation Method, the highway route design is reasonable, simple to operate, and reaction condition is gentle, and raw material is easy to get, gained impurity purity up to more than 99%,
The reference substance that can be studied as glycylglutamine impurity uses, for the qualitative and quantitative analysis of impurity, to glycyl paddy
Glutamine bulk drug quality research has positive effect.
Brief description of the drawings
Fig. 1 is the high resolution mass spectrum figure of glycyl glycyl-L-glutamine in the embodiment of the present invention 1;
Fig. 2 is the 1H-NMR spectrograms of glycyl glycyl-L-glutamine in the embodiment of the present invention 1;
Fig. 3 is the high-efficient liquid phase chromatogram of glycyl glycyl-L-glutamine in the embodiment of the present invention 1;
Fig. 4 is the high-efficient liquid phase chromatogram of glycyl glycyl-L-glutamine in the embodiment of the present invention 2;
Fig. 5 is the high-efficient liquid phase chromatogram of glycyl glycyl-L-glutamine in the embodiment of the present invention 3;
Fig. 6 is the high-efficient liquid phase chromatogram of glycyl glycyl-L-glutamine in the embodiment of the present invention 4.
Embodiment
With reference to embodiment, the present invention will be further described, but does not limit the present invention.
All raw materials used in embodiment are purchased in market unless otherwise specified.
Embodiment 1
(1) preparation of N-Pht- glycine (compound 3):
The triethylamine of 7.5g glycine, 14.8g phthalic anhydrides and 0.4mL is added in 50mL toluene, is heated to reflux 7h, is down to
Room temperature, add concentrated hydrochloric acid and adjust pH value to 3~4, filter, wash, dry, obtain white solid 19.6g, the sweet ammonia of as N-Pht-
Acid, yield 96%.
(2) preparation of N-Pht- glycyl chlorides (compound 4):
12.0g compounds 3 are added in 60mL toluene, are stirred lower addition 9.0g thionyl chlorides, after being heated to reflux 3h, are subtracted
Pressure is concentrated to dryness, re crystallization from toluene, is dried in vacuo to obtain 11.1g pale yellow crystals, and as N-Pht- glycyl chlorides, yield is
85%.
(3) preparation of N-Pht- glycyl glycyl-L-glutamine (compound 6):
1.7g sodium hydroxide is dissolved in 20mL water, adds 10mL toluene, is cooled to 0 DEG C, adds 7.0g glycyl-L-
Glutamine (compound 5), the toluene solution of 8.6g compounds 4 is added dropwise, while 25% sodium hydroxide solution is added dropwise, be added dropwise
Cheng Wendu keeps pH value 7~8 at 0 ± 5 DEG C.Drop finishes, and 1h is stirred at room temperature, and stands, liquid separation.Aqueous phase hydrochloric acid adjust pH value be 2~
After 3, continue to stir 1h, filter, dry, obtain 9.6g white solids, yield 71%.
(4) preparation of glycyl glycyl-L-glutamine (compound 1):
6.0g N-Pht- glycyl glycyl-L-glutamines (compound 6) are suspended in 18mL methanol, are warming up to
45 DEG C, 1.0g hydrazine hydrates are added dropwise successively, 1.7g triethylamines, reacts 4h at 42 ± 2 DEG C, obtains white suspension.Into reaction solution
The methanol solution of butanedioic acid is added dropwise, it is to 5~6 to adjust pH value, is down to room temperature after stirring 10min, filters to obtain filter cake.Filter cake 9.0g
Water washing, is filtered, and merging filtrate is slowly added dropwise 30mL methanol into filtrate, 0 DEG C of stirring 1h, is filtered, dry white solid
3.3g, as glycyl glycyl-L-glutamine crude product, yield 83%.
3.0g crude products are suspended in 9mL water, are warming up to 45 DEG C of dissolvings, add 0.1g activated carbon decolorizing 0.5h, are filtered, to filter
It is slowly added dropwise 27mL methanol in liquid, 5 ± 5 DEG C of stirring 1h, filters, dry white solid 2.3g, as glycyl glycyl-L-
Glutamy, yield 76%, purity 99.3%.
1H-NMR(600MHz,D2O,ppm):4.20 (1H, m), 4.02 (2H, m), 3.90 (2H, m), 2.30 (2H, m),
2.12,1.94(2H,each m).ESI-MS:[M+H]+261.1。
Embodiment 2
(1) preparation of N-Pht- glycine (compound 3) is the same as embodiment 1.
(2) preparation of N-Pht- glycyl chlorides (compound 4):
12.0g compounds (3) are added in 75mL toluene, are stirred lower addition 10.4g thionyl chlorides, are heated to reflux 3h
Afterwards, dry, re crystallization from toluene is concentrated under reduced pressure into, is dried in vacuo to obtain 11.8g pale yellow crystals, yield 90%.
(3) preparation of N-Pht- glycyl glycyl-L-glutamine (compound 6):
2.0g sodium hydroxide is dissolved in 20mL water, adds 10mL toluene, is cooled to 3 DEG C, adds 7.0g glycyl-L-
Glutamine, the toluene solution of 8.6g compounds 4 is added dropwise, while 25% sodium hydroxide solution is added dropwise, process temperature is added dropwise 3
± 5 DEG C, pH value is 7~8.Drop, which finishes, is stirred at room temperature 1h, stands, liquid separation.After aqueous phase hydrochloric acid tune pH value is 2~3, continue to stir
1h, filter, dry, obtain white solid 8.8g, yield 65%.
(4) preparation of glycyl glycyl-L-glutamine (compound 1):
6.0g N-Pht- glycyl glycyl-L-glutamines (compound 6) are suspended in 18mL methanol, are warming up to
45 DEG C, 1.0g hydrazine hydrates are added dropwise successively, 1.7g triethylamines, reacts 5h at 45 ± 2 DEG C, obtains white suspension.Dripped into reaction solution
The methanol solution of adding citric acid to pH value is 5~6, is down to room temperature after stirring 10min, filters to obtain filter cake.Filter cake is washed with 12g
To wash, filter, merging filtrate is slowly added dropwise 30mL methanol into filtrate, 0 DEG C of stirring 1h, filters, dry white solid 3.4g,
As glycyl glycyl-L-glutamine crude product, yield 85%.
3.0g crude products are suspended in 9mL water, are warming up to 45 DEG C of dissolvings, add 0.1g activated carbon decolorizing 0.5h, are filtered, to filter
It is slowly added dropwise 54mL methanol in liquid, 5 ± 5 DEG C of stirring 1h, filters, dry white solid 2.4g, as glycyl glycyl-L-
Glutamine, yield 80%, purity 99.2%.
Embodiment 3
(1) preparation of N-Pht- glycine (compound 3) is the same as embodiment 1.
(2) preparation of N-Pht- glycyl chlorides (compound 4):
12g compounds (3) are added in 60mL toluene, stir lower addition 11.8g thionyl chlorides, after being heated to reflux 5h,
Dry, re crystallization from toluene is concentrated under reduced pressure into, is dried in vacuo to obtain 11.0g pale yellow crystals, yield 84%.
(3) preparation of N-Pht- glycyl glycyl-L-glutamine (compound 6):
1.6g sodium hydroxide is dissolved in 20mL water, adds 10mL toluene, is cooled to 4 DEG C, adds 7.0g glycyl-L-
Glutamine, the toluene solution of 8.6g compounds 4 is added dropwise, while 25% sodium hydroxide solution is added dropwise, process temperature is added dropwise 5
± 5 DEG C, pH value is 7~8.Drop, which finishes, is stirred at room temperature 1h, stands, liquid separation.After aqueous phase hydrochloric acid tune pH value is 2~3, continue to stir
0.5h, filter, dry, obtain white solid 9.1g, yield 67%.
(4) preparation of glycyl glycyl-L-glutamine (compound 1):
6.0g N-Pht- glycyl glycyl-L-glutamines (compound 6) are suspended in 18mL methanol, are warming up to
45 DEG C, 1.1g hydrazine hydrates are added dropwise successively, 1.8g triethylamines, reacts 6h at 45 ± 2 DEG C, obtains white suspension.Dripped into reaction solution
Tartarated methanol solution to pH value is 5~6, is down to room temperature after stirring 10min, filters to obtain filter cake.Filter cake is washed with 12g
To wash, filter, merging filtrate is slowly added dropwise 80mL methanol into filtrate, 0 DEG C of stirring 1h, filters, dry white solid 3.2g,
As glycyl glycyl-L-glutamine crude product, yield 80%.
3.0g crude products are suspended in 6mL water, are warming up to 50 DEG C of dissolvings, add 0.1g activated carbon decolorizing 0.5h, are filtered, to filter
It is slowly added dropwise 12mL methanol in liquid, 5 ± 5 DEG C of stirring 1h, filters, dry white solid 2.3g, as glycyl glycyl-L-
Glutamine, yield 77%, purity 99.2%.
Embodiment 4
(1) preparation of N-Pht- glycine (compound 3) is the same as embodiment 1.
(2) preparation of N-Pht- glycyl chlorides (compound 4):
12.0g compounds (3) are added in 90mL toluene, are stirred lower addition 13.8g thionyl chlorides, are heated to reflux 7h
Afterwards, dry, re crystallization from toluene is concentrated under reduced pressure into, is dried in vacuo to obtain 10.6g pale yellow crystals, yield 91%.
(3) preparation of N-Pht- glycyl glycyl-L-glutamine (compound 6):
2.2g sodium hydroxide is dissolved in 20mL water, adds 10mL toluene, is cooled to -1 DEG C, adds 7g glycyl-L-
Glutamine, the toluene solution of 8.6g compounds 4 is added dropwise, while 25% sodium hydroxide solution is added dropwise, process temperature is added dropwise 2
± 5 DEG C, pH value is 7~8.Drop, which finishes, is stirred at room temperature 2h, stands, liquid separation.After aqueous phase hydrochloric acid tune pH value is 2~3, continue to stir
1h, filter, dry, obtain white solid 8.4g, yield 62%.
(4) preparation of glycyl glycyl-L-glutamine (compound 1):
6g N-Pht- glycyl glycyl-L-glutamines (compound 6) are suspended in 18mL methanol, are warming up to 45
DEG C, 1.1g hydrazine hydrates are added dropwise successively, 1.9g triethylamines, reacts 7h at 45 ± 2 DEG C, obtains white suspension.It is added dropwise into reaction solution
The methanol solution of malic acid is down to room temperature after stirring 10min, filters to obtain filter cake to pH value 5~6.Filter cake 18g water washings, take out
Filter, merging filtrate are slowly added dropwise 70mL methanol into filtrate, 0 DEG C of stirring 1h, filter, dry white solid 3.1g, as sweet
Aminoacyl glycyl-L-glutamine crude product, yield 76%.
3.0g crude products are suspended in 6mL water, are warming up to 50 DEG C of dissolvings, add 0.1g activated carbon decolorizing 0.5h, are filtered, to filter
It is slowly added dropwise 36mL methanol in liquid, 5 ± 5 DEG C of stirring 1h, filters, dry white solid 2.0g, as glycyl glycyl-L-
Glutamine, yield 67%, purity 99.1%.
Claims (10)
- A kind of 1. preparation method of glycylglutamine impurity, it is characterised in that:Step is as follows:(1) glycine, phthalic anhydride and triethylamine are added in toluene, are heated to reflux 5~10h, then cool, added concentrated hydrochloric acid and adjust PH value is saved to 3~4, room temperature is down to, filters, obtain N-Pht- glycine;(2) N-Pht- glycine is added in toluene, adds thionyl chloride, heating reflux reaction, reaction is finished, is evaporated off molten Agent, using re crystallization from toluene, obtain N-Pht- glycyl chlorides;(3) toluene is added into sodium hydroxide solution, is cooled, adds glycyl-L-glutamine, N-Pht- glycyl chlorides are added dropwise Toluene solution, while be added dropwise sodium hydroxide solution maintain pH value 7~8;It is added dropwise, 0.5~2h is stirred at room temperature, stands, Liquid separation, aqueous phase are continued 0.5~2h of stirring and crystallizing, are filtered, obtain the sweet ammonia of N-Pht- glycyl with after concentrated hydrochloric acid regulation pH value to 2~3 Acyl-Glu;(4) N-Pht- glycyl glycyl-L-glutamines are suspended in methanol, reacted under hydrazine hydrate, triethylamine, then The methanol solution of organic acid is added dropwise, filters, filter cake is washed with water, and methanol is added dropwise in filtrate, filters, obtains glycyl glycyl-L- Glutamine crude product, crude product obtain glycyl glycyl-L-glutamine through water, refining methanol.
- 2. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:Step (1) is described Glycine, the mol ratio of phthalic anhydride and triethylamine be 1:1~1.2:0.05~0.2.
- 3. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:Step (2) is described N-Pht- glycine and thionyl chloride mol ratio be 1:1.2~2.
- 4. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:Step (2) is described Reflux time be 3~7h.
- 5. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:In step (3), to Toluene is added in sodium hydroxide solution, is cooled, adds glycyl-L-glutamine, the toluene that N-Pht- glycyl chlorides are added dropwise is molten Liquid;Wherein, the mol ratio of glycyl-L-glutamine and sodium hydroxide in sodium hydroxide solution is 1:1~1.5, N- is added dropwise Temperature is -5~10 DEG C during the toluene solution of Pht- glycyl chlorides.
- 6. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:Step (4) is described N-Pht- glycyl glycyl-L-glutamine, hydrazine hydrate, triethylamine mol ratio be 1:1.05~1.1:1.1~1.2.
- 7. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:Step (4) is described Reacted under hydrazine hydrate, triethylamine, reaction temperature be 40~50 DEG C, the reaction time is 4~7h.
- 8. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:In step (4), drop The methanol solution of organic acid is added to adjust pH value to 5~6, described organic acid is formic acid, acetic acid, citric acid, tartaric acid, apple One or more in acid, maleic acid, fumaric acid, lactic acid, butanedioic acid or methanesulfonic acid.
- 9. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:Step (4) is described Filter cake be washed with water, be added dropwise methanol in filtrate, the dosage of water is that N-Pht- glycyl glycyl-L-glutamines feed intake quality 1.5~3 times, the volume ratio of water and methanol is 1:2~6.
- 10. the preparation method of glycylglutamine impurity according to claim 1, it is characterised in that:Step (4) is described Crude product be specially through water, refining methanol:Crude product is suspended in water, rising temperature for dissolving, after activated carbon decolorizing, methanol is added dropwise, Filter;The quality of described water is 2~3 times of crude product quality, and the volume ratio of water and methanol is 1:2~6.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711138062.9A CN107857795A (en) | 2017-11-16 | 2017-11-16 | The preparation method of glycylglutamine impurity |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711138062.9A CN107857795A (en) | 2017-11-16 | 2017-11-16 | The preparation method of glycylglutamine impurity |
Publications (1)
Publication Number | Publication Date |
---|---|
CN107857795A true CN107857795A (en) | 2018-03-30 |
Family
ID=61703099
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711138062.9A Pending CN107857795A (en) | 2017-11-16 | 2017-11-16 | The preparation method of glycylglutamine impurity |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107857795A (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103626839A (en) * | 2013-12-19 | 2014-03-12 | 济南诚汇双达化工有限公司 | Preparation method of N(2)-L-alanyl-L-glutamine |
CN103936824A (en) * | 2014-05-11 | 2014-07-23 | 孔凯明 | Green preparation method of phthalylglycyl-L-glutamine |
-
2017
- 2017-11-16 CN CN201711138062.9A patent/CN107857795A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103626839A (en) * | 2013-12-19 | 2014-03-12 | 济南诚汇双达化工有限公司 | Preparation method of N(2)-L-alanyl-L-glutamine |
CN103936824A (en) * | 2014-05-11 | 2014-07-23 | 孔凯明 | Green preparation method of phthalylglycyl-L-glutamine |
Non-Patent Citations (2)
Title |
---|
张哲等: "甘氨酰-L-谷氨酰胺的合成", 《化学试剂》 * |
车丽慧: "甘氨酰谷氨酰胺的生产工艺优化研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104860894B (en) | Method for preparing cardiotonic drug LCZ696 | |
CN103664921B (en) | A kind of Azilsartan crystal formation A and preparation method thereof | |
CN108727334B (en) | Production process of dabigatran etexilate mesylate | |
CN105085373B (en) | A kind of purification process to Apremilast product | |
CN113121416A (en) | Preparation method of lefenacin | |
CN1109017C (en) | Preparation of 1.1-cyclohexyl oxalic amide | |
CN105669651B (en) | A kind of preparation technology of dabigatran etexilate methanesulfonate | |
CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
CN107857795A (en) | The preparation method of glycylglutamine impurity | |
CN115073490A (en) | Preparation method of Ruogeli and intermediate thereof | |
CN109694330A (en) | A kind of preparation method of acid | |
CN115197150B (en) | Preparation method of L-carnosine | |
CN114773176B (en) | Chlorpheniramine maleate impurity and preparation method and application thereof | |
CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
CN110015978B (en) | Synthesis method of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine | |
CN114835654B (en) | Preparation method of peramivir key intermediate | |
CN114262359A (en) | Preparation method of carfilzomib impurities | |
CN114478837A (en) | Preparation method of sugammadex sodium derivative | |
CN109824546B (en) | BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid condensation impurity and preparation method thereof | |
CN108084085B (en) | A kind of preparation method of N- (the chloro- 4- of 3- (2- pyridomethoxy) phenyl) -2- cyanoacetamide | |
CN113480480A (en) | Synthesis method of (R) -5' -methoxylapatin | |
CN108947908B (en) | New intermediate of brivaracetam with imidazole ring and synthesis method and application thereof | |
CN106432059A (en) | Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine | |
CN103923063B (en) | Crystal formation of a kind of SYR-322 and preparation method thereof | |
CN111333552B (en) | Synthesis method of beta-benzo amino acid compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180330 |