CN109293722B - Azithromycin related substance and preparation method thereof - Google Patents
Azithromycin related substance and preparation method thereof Download PDFInfo
- Publication number
- CN109293722B CN109293722B CN201811187091.9A CN201811187091A CN109293722B CN 109293722 B CN109293722 B CN 109293722B CN 201811187091 A CN201811187091 A CN 201811187091A CN 109293722 B CN109293722 B CN 109293722B
- Authority
- CN
- China
- Prior art keywords
- azithromycin
- reaction
- related substance
- catalyst
- platinum carbon
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application relates to an azithromycin related substance and a preparation method thereof, belonging to the technical field of synthesis of heterocyclic compounds. Dissolving erythromycin imine ether serving as a raw material, adjusting the pH value to 4-5, adding platinum carbon serving as a catalyst, introducing hydrogen, maintaining the pressure and carrying out heat preservation reaction, wherein the pretreatment is carried out before the platinum carbon serving as the catalyst is used, and the pretreatment comprises the following steps: stirring 5% platinum carbon in water, adding metal ions, and pulping for half an hour; filtering the catalyst, recovering the feed liquid, drying, adding acetone, adding formic acid formaldehyde, controlling the pH value to be 5-6, preserving the temperature and carrying out N methylation reaction; after the reaction is finished, a brine layer is taken and separated, and an organic layer is crystallized by adding water to obtain a crude product; purifying to obtain the finished product. The application is applied to the synthesis of azithromycin and related substances thereof, not only can be used as a reference substance to be applied to qualitative and quantitative analysis of azithromycin impurities, but also is beneficial to improving the medication safety of the azithromycin.
Description
Technical Field
The application relates to an azithromycin related substance, namely impurity P, and a preparation method thereof, belonging to the technical field of synthesis of heterocyclic compounds.
Background
Azithromycin (Azithromycin) is the first semi-synthetic aza pentadecentricular macrolide antibiotic developed by pharmaceutical company of Crodilapine as the second generation erythromycin product. The azithromycin is obtained by oximation of erythromycin A9-ketone, and then a series of reactions such as Beckmann rearrangement, hydrogenation reduction, N-methylation and the like. This structural difference hinders the reaction of forming hemiketals internally, making azithromycin more acid stable than erythromycin a. Azithromycin and erythromycin have commonality in an antibacterial mechanism, and are combined with a ribosome 50S subunit in a bacterial cell to block a bacterial transpeptidation process and inhibit the synthesis of proteins depending on RNA so as to achieve an antibacterial effect. However, due to the change of the structure, azithromycin has a wider antibacterial spectrum than erythromycin, can inhibit various gram-positive cocci, mycoplasma, chlamydia and legionella pneumophila, particularly has good antibacterial activity on some important gram-negative bacilli such as haemophilus influenzae and the like, and makes up the defect of poor effect of macrolides on haemophilus.
It is widely used in respiratory system, urinary system and skin soft tissue infection, etc. and has been approved by FDA in the United states to replace penicillin drugs as first-line drugs of anti-infective drugs, and can also treat mycobacterial infection of AIDS patients. Another outstanding advantage of azithromycin is its unique pharmacokinetic properties, which upon absorption can be transferred to the site of infection to achieve very high tissue concentrations. The azithromycin also has the advantages of long half-life period, less administration times, shorter treatment course, low adverse reaction incidence rate and the like, and is a good variety in the international anti-infective market.
In the research on related substances of azithromycin, including the Chinese pharmacopoeia 2015 edition, the United states pharmacopoeia USP40 edition and the European pharmacopoeia EP9.0 edition, the structural formulas of all impurities are described in detail, the relative retention peak-out time, the content calculation correction factor and the control limit are provided, but the introduction of the impurity P shows that the impurity with an unknown structure is provided, the relative retention peak-out time is 0.92 times, and the control limit is 0.2%. Therefore, if the impurity can be prepared into a pure product and subjected to structure identification, the method is greatly helpful for ensuring the safety of clinical medication and filling the blank of azithromycin related substance research.
The present application was made based on this.
Disclosure of Invention
In view of the above-mentioned blank in the research of related substances of azithromycin, the present application firstly provides the structural formula of the related substance, i.e. the impurity P.
An azithromycin related substance, which is an impurity P in European pharmacopoeia and has a structural formula as follows:
the azithromycin impurity P belongs to unknown impurities in European pharmacopoeia, and the obtained impurities are subjected to structure identification to obtain specific structures, so that the blank of an azithromycin related substance database is filled, and an important basis is provided for the medication safety of azithromycin, therefore, the structural formula of the impurity P is confirmed, meanwhile, the research on how the azithromycin impurity P is generated is also carried out, and the synthetic route is summarized as follows.
A preparation method of azithromycin related substances comprises the following steps: (1) dissolving erythromycin imine ether serving as a raw material in methanol, adjusting the pH value to 4-5 by using hydrochloric acid and the like, adding platinum carbon serving as a catalyst, putting the mixture into an autoclave, introducing hydrogen into the autoclave at the pressure of 1.0-1.2MPa, maintaining the pressure, and carrying out heat preservation reaction, wherein the platinum carbon is pretreated before being used as the catalyst, and the pretreatment comprises the following steps: stirring 5% platinum carbon in water, adding metal ions, and pulping for half an hour; (2) filtering the catalyst, recovering the feed liquid, drying, adding acetone, adding formic acid formaldehyde, controlling the pH value to be 5-6, preserving the temperature and carrying out N methylation reaction; (3) after the reaction is finished, adjusting alkali, removing a saline layer, and adding water into an organic layer for crystallization to obtain a crude product; (4) and purifying the crude product to obtain a finished product.
After mass production data research and analysis, we found that: the azithromycin impurity P has a certain correlation with the activity of platinum carbon. According to the method, firstly, platinum carbon is specially treated, 5% of platinum carbon is stirred in water and added with metal ions for pulping treatment, and then the platinum carbon is used as a catalyst, the platinum carbon is inactivated under the specific condition to cause a large amount of impurities P, according to the phenomenon, a platinum carbon special treatment process is designed and then used for hydrogenation reaction of erythromycin imino ether, finally, azithromycin impurities P with the content of 30-40% are obtained, after column chromatography separation and purification, the impurities P with the content of more than 95% are obtained, nuclear magnetic resonance, mass spectrum, infrared spectrum and ultraviolet spectrum analysis are carried out on a target product, and the structural formula of the target product is finally determined.
When platinum carbon pretreatment is carried out, usable metal ions are tested, metal ions with excellent reaction effect can be screened, and the result shows that: the metal ion comprises Ca2+、Cu2+、Fe3+Etc., and is preferably Fe3+。
When the platinum carbon pretreatment is carried out, the addition amount of metal ions is tested, and the result shows that: when the amount of the metal ions added is 0.1 to 1%, preferably 0.5% by weight of platinum carbon, relatively good generation of impurity P can be obtained.
On the basis of the above research, we also studied specific reaction parameters of each step, as follows:
experiments are carried out on specific parameters of the pressure-maintaining and heat-preserving reaction in the step (1), and the results show that: when the pressure is controlled at 1.0-1.2MPa, the temperature is 55-60 ℃, and the reaction time is 8-12h, the reaction can be fully and stably carried out.
The specific parameters of the N methylation reaction in the step (2) are researched, and the results show that: when the reaction temperature is controlled at 40-50 ℃ and the reaction time is 20-30h, the reaction can be carried out fully and stably.
After the whole reaction is finished, the forming process of the crude product is researched, and the result shows that when the reaction is finished, the pH value is adjusted to 10-11, standing and layering are carried out, an organic layer is taken, the temperature is increased to 40-45 ℃, water is slowly dripped until crystals are separated out, the temperature is reduced to 30-35 ℃, water is continuously dripped until the crystals are completely separated out, and the crude product is obtained after filtration and drying.
We have also studied the purification and found that when the purification is carried out by liquid preparative chromatography, a good purification effect can be obtained, wherein the flow rate during the purification is 50.0mL/min,the eluent is 1.8g/LK2HPO4Solution: (acetonitrile-methanol-3: 1) 30:70, the purity of the finished product obtained from the crude product is as high as more than 95%.
The synthesis path of azithromycin related substances, namely impurity P is shown as formula 1, and it can be seen from the synthesis path that the activity is reduced to some extent after the platinum carbon is treated by metal ions, the carbon-nitrogen double bond is not reduced, the double bond is subjected to imine hydrolysis under an acidic condition, and the formed amino is subjected to two methyl groups under the action of formic acid formaldehyde to obtain a target product.
The method carries out infrared spectrum, nuclear magnetic resonance and mass spectrum analysis on the target product, and confirms the structure of the target product according to the detection result.
The method has the advantages that the structure of the azithromycin impurity P is determined, the purity of the prepared related substances is as high as more than 95%, the related substances can be used as reference substances for qualitative and quantitative analysis of the azithromycin impurity, the pharmaceutical safety of the azithromycin is favorably improved, and the blank of azithromycin impurity research is filled.
Drawings
Figure 1 is an infrared spectrum of an azithromycin related substance (i.e., impurity P) in the present application;
FIG. 2 shows the NMR spectrum of azithromycin related substance (i.e. impurity P) in the present application: (1H-NMR);
FIG. 3 shows the method for preparing azithromycin related substance (i.e. impurity P) in the present application13C-NMR carbon spectrum;
figure 4 is a DEPT135 ° carbon spectrum of an azithromycin related substance (i.e., impurity P) of the present application;
FIG. 5 shows the method for preparing azithromycin related substance (i.e. impurity P) in the present application1H-1HCOSY-related spectra;
FIG. 6 is an HSQC correlation spectrum of an azithromycin related substance (i.e., impurity P) in the present application;
figure 7 is an HMBC correlation spectrum of an azithromycin related substance (i.e., impurity P) in the present application.
Detailed Description
The raw material used in the embodiment is erythromycin 6, 9-imino ether, and the synthesis of the azithromycin is prepared by taking erythromycin thiocyanate as a raw material and carrying out two-step reactions of oximation and rearrangement reaction, which belongs to a general technology in the azithromycin synthesis process and is not described in detail.
Example 1: pretreatment of platinum carbon
The method comprises the following steps: 50g of platinum carbon (platinum content: 5%) is taken, 300ml of water is added, stirring is carried out, 0.72g of ferric trichloride is added, pulping is carried out for 0.5 hour, and filtering is carried out to obtain the treated platinum carbon catalyst.
The second method comprises the following steps: 50g of platinum carbon (platinum content: 5%) is taken, 300ml of water is added, stirring is carried out, 0.69g of calcium chloride is added, pulping is carried out for 0.5 hour, and filtering is carried out to obtain the treated platinum carbon catalyst.
The third method comprises the following steps: 50g of platinum carbon (platinum content: 5%) is taken, 300ml of water is added, stirring is carried out, 0.53g of copper chloride is added, pulping is carried out for 0.5 hour, and filtering is carried out, thus obtaining the treated platinum carbon catalyst.
The three metal ions are tested to find that the three metal ions can achieve good use effects, the rest are not detailed one by one, and the following cases respectively take the three metal ions as representatives to respectively realize the synthesis of the azithromycin related substances, which is specifically shown in examples 2-4.
Example 2
And (3) taking 30g of erythromycin 6, 9-imino ether, adding 200ml of methanol, stirring for dissolving, and adjusting the pH value to 4-5 by using hydrochloric acid. Platinum-carbon treated in example 1 according to method one was charged into the autoclave, and then the dissolved feed liquid was charged into the autoclave together to start the hydrogenation operation. Keeping the hydrogen pressure between 1.0 and 1.2MPa, slowly heating to 55 to 60 ℃, and reacting for 8 to 12 hours. After the reaction, the hydrogenation feed liquid is taken out, the catalyst is removed by filtration, and the feed liquid is recovered to be dry. Dissolving the mixture in 100ml of acetone, adding 10g of formic acid and 15g of formaldehyde (37% aqueous solution), adjusting the pH value to 5-6 by using sodium hydroxide (30% aqueous solution), and preserving the temperature for 20-30 hours at 40-50 ℃. After the reaction is finished, adjusting the pH value to 10-11 by using sodium hydroxide (30% aqueous solution). Standing for layering, taking an acetone organic layer, heating to 40-45 ℃, slowly dripping water until crystals are separated out, cooling to 30-35 ℃, and continuously dripping water until the crystals are completely separated out, wherein the water addition amount in two times is 200 ml. Filtration and drying gave 26.8g of a white solid. And (5) performing HPLC liquid phase analysis, wherein the content of azithromycin related substances, namely impurity P, is 31.6%.
Example 3
And (3) taking 30g of erythromycin 6, 9-imino ether, adding 200ml of methanol, stirring for dissolving, and adjusting the pH value to 4-5 by using hydrochloric acid. Platinum-carbon treated according to method two in example 1 was charged into the autoclave, and then the dissolved feed liquid was charged into the autoclave together, and the hydrogenation operation was started. Keeping the hydrogen pressure between 1.0 and 1.2MPa, slowly heating to 55 to 60 ℃, and reacting for 8 to 12 hours. After the reaction, the hydrogenation feed liquid is taken out, the catalyst is removed by filtration, and the feed liquid is recovered to be dry. Dissolving the mixture in 100ml of acetone, adding 10g of formic acid and 15g of formaldehyde (37% aqueous solution), adjusting the pH value to 5-6 by using sodium hydroxide (30% aqueous solution), and preserving the temperature for 20-30 hours at 40-50 ℃. After the reaction is finished, adjusting the pH value to 10-11 by using sodium hydroxide (30% aqueous solution). Standing for layering, taking an acetone organic layer, heating to 40-45 ℃, slowly dripping water until crystals are separated out, cooling to 30-35 ℃, and continuously dripping water until the crystals are completely separated out, wherein the water addition amount in two times is 200 ml. Filtration and drying gave 25.6g of a white solid. And (5) performing HPLC liquid phase analysis, wherein the content of azithromycin related substances, namely impurity P, is 22.3%.
Example 4
And (3) taking 30g of erythromycin 6, 9-imino ether, adding 200ml of methanol, stirring for dissolving, and adjusting the pH value to 4-5 by using hydrochloric acid. Platinum-carbon treated in the third method of example 1 was charged into the autoclave, and then the dissolved feed liquid was charged into the autoclave together to start the hydrogenation operation. Keeping the hydrogen pressure between 1.0 and 1.2MPa, slowly heating to 55 to 60 ℃, and reacting for 8 to 12 hours. After the reaction, the hydrogenation feed liquid is taken out, the catalyst is removed by filtration, and the feed liquid is recovered to be dry. Dissolving the mixture in 100ml of acetone, adding 10g of formic acid and 15g of formaldehyde (37% aqueous solution), adjusting the pH value to 5-6 by using sodium hydroxide (30% aqueous solution), and preserving the temperature for 20-30 hours at 40-50 ℃. After the reaction is finished, adjusting the pH value to 10-11 by using sodium hydroxide (30% aqueous solution). Standing for layering, taking an acetone organic layer, heating to 40-45 ℃, slowly dripping water until crystals are separated out, cooling to 30-35 ℃, and continuously dripping water until the crystals are completely separated out, wherein the water addition amount in two times is 200 ml. Filtration and drying gave 24.5g of a white solid. And (4) performing HPLC liquid phase analysis, wherein the content of azithromycin related substances, namely impurity P, is 30.2%.
Example 5: separation and purification of azithromycin impurity P
The impurity P was extracted and purified using a liquid preparative chromatography column, and specific column conditions are shown in table 1.
TABLE 1 Azithromycin impurity P liquid phase preparative chromatographic conditions
Laboratory apparatus | 50DAC prepares system |
Filler material | RP18(C18 8μm) |
Flow rate of flow | 50.0mL/min |
Detection wavelength | 210nm |
Isocratic elution | 1.8g/L K2HPO4Solution: (acetonitrile-methanol-3: 1) -30: 70 |
And (3) sampling a crude product solution, collecting a target peak with RT (about 86 min), collecting eluent with the purity meeting the requirement, concentrating and evaporating the solvent, washing the rest solid with water to remove salt, and freeze-drying. This impurity was obtained as a white solid with an HPLC purity of greater than 99.1%.
Mass spectrometry analysis: is divided intoA molecular weight of 776.5, and a predicted molecular formula C39H72N2O13And (4) the same.
The infrared spectroscopic analysis is shown in Table 2 and FIG. 1.
TABLE 2 infrared analysis table for azithromycin impurity P
Absorption Peak (cm)-1) | Vibration type and attribution | Absorption peak intensity | Remarks for note |
3449 | υO-H | w | O-H stretching vibration on |
2975,2940 | υC-H | m | Saturated C-H stretching vibration |
1729 | υC=O | m | Stretching vibration of C ═ O on ester group |
1458,1381 | δC-H | m | Methyl C-H bending vibration |
1187,1165 | υC-O | vs | C-O stretching vibration on ester group |
1002-1112 | υC-O,C-N | vs | C-O and C-N stretching vibration |
The infrared spectrogram of the sample shows characteristic absorption of the molecules containing hydroxyl, ester group, saturated C-H bond, amine and other groups, and shows that the molecules of the sample contain the hydroxyl, ester group, methyl, amine and other groups and accord with the structural formula of the sample.
TABLE 3 and TABLE 4 shows NMR spectra1H-NMR), carbon spectrum (13C-NMR, DEPT135 ℃ and the related spectrum: (1H-1HCOSY, HMQC, HMBC) data, corresponding spectra are shown in fig. 2-7.
TABLE 31H-NMR and1H-1h COSY data
TABLE 413C-NMR, DEPT135 °, HMQC, HMBC data
Azithromycin impurity P nuclear magnetic resonance hydrogen spectrum (1H-NMR, FIG. 2), carbon spectrum: (13C-NMR (FIG. 3, DEPT135 ℃ C.) (FIG. 4) and the correlation spectrum: (1H-1H COSY, HSQC, HMBC, i.e. fig. 5, 6, 7) corroborate the structure of the samples.
The above description is provided for the purpose of describing the preferred embodiments of the present invention in more detail, and it should not be construed that the embodiments of the present invention are limited to the description above, and it will be apparent to those skilled in the art that the present invention can be implemented in many different forms without departing from the spirit and scope of the present invention.
Claims (7)
1. The preparation method of the azithromycin related substance is characterized by comprising the following steps: (1) dissolving erythromycin 6, 9-imino ether serving as a raw material, adjusting the pH value to 4-5, adding platinum carbon serving as a catalyst, and carrying out heat preservation reaction under a set pressure, wherein the pretreatment is carried out before the platinum carbon serving as the catalyst is used, and comprises the following steps: stirring 5% platinum carbon in water and adding metal ions, wherein the metal ions adopt Ca2+、Cu2+、Fe3+Any one of, pulping; (2) filtering the catalyst, recovering the feed liquid, drying, adding acetone, adding formic acid and formaldehyde, controlling the pH value to be 5-6, preserving the heat, and carrying out heat treatmentCarrying out N methylation reaction; (3) after the reaction is finished, adding water into the organic layer for crystallization to obtain a crude product; (4) and (3) purifying the crude product to obtain a finished product, wherein the related substances are as follows:
2. the method for producing an azithromycin-related substance according to claim 1, wherein: in the step (1), the set pressure is 1.0-1.2MPa, the reaction temperature in the heat preservation reaction is 55-60 ℃, and the reaction time is 8-12 h.
3. The method for producing an azithromycin-related substance according to claim 1, wherein: in the pretreatment of the step (1), the input amount of metal ions in the pretreatment is 0.1-1% of the weight of platinum and carbon.
4. The method for producing an azithromycin-related substance according to claim 3, wherein: the input amount of the metal ions is 0.5 percent of the weight of the platinum carbon.
5. The method for producing an azithromycin-related substance according to claim 1, wherein: in the N methylation reaction in the step (2), the reaction temperature is 40-50 ℃, and the reaction time is 20-30 hours.
6. The preparation method of azithromycin-related substance according to claim 1, wherein in the step (3), after the reaction is finished, the pH value is adjusted to 10-11, the mixture is kept standing for layering, an organic layer is taken, the temperature is raised to 40-45 ℃, water is slowly dripped until crystals are separated out, the temperature is lowered to 30-35 ℃, water is continuously dripped until the crystals are completely separated out, and a crude product is obtained after filtration and drying.
7. The azithromycin related substance according to claim 1The preparation method of (5), wherein in the step (4), the purification adopts a liquid preparative chromatography column separation method: the flow rate was 50.0mL/min and the eluent was 1.8g/L K2HPO4Solution: (acetonitrile-methanol-3: 1) -30: 70.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811187091.9A CN109293722B (en) | 2018-10-12 | 2018-10-12 | Azithromycin related substance and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811187091.9A CN109293722B (en) | 2018-10-12 | 2018-10-12 | Azithromycin related substance and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109293722A CN109293722A (en) | 2019-02-01 |
CN109293722B true CN109293722B (en) | 2020-05-22 |
Family
ID=65162326
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811187091.9A Active CN109293722B (en) | 2018-10-12 | 2018-10-12 | Azithromycin related substance and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109293722B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112629990A (en) * | 2021-01-24 | 2021-04-09 | 深圳博泰尔生物技术有限公司 | Azithromycin reference substance and preparation method thereof |
CN113817005A (en) * | 2021-10-14 | 2021-12-21 | 浙江国邦药业有限公司 | Azithromycin related substance and synthesis method thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101712703B (en) * | 2009-11-18 | 2013-08-21 | 上海华理生物医药有限公司 | Method for preparing azithromycin and method for preparing intermediate of azithromycin |
CN103087125B (en) * | 2013-02-06 | 2015-12-02 | 浙江国邦药业有限公司 | Prepare the processing method that Azythromycin is treated different things alike |
CN108727445B (en) * | 2018-06-29 | 2021-06-11 | 宜昌东阳光生化制药有限公司 | Synthesis method of azithromycin impurity F |
-
2018
- 2018-10-12 CN CN201811187091.9A patent/CN109293722B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN109293722A (en) | 2019-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20020007049A1 (en) | Ethanolate of azithromycin, process for manufacture, and pharmaceutical compositions thereof | |
EP4151645A2 (en) | Separation of 2'-fl from a fermentation broth | |
EP1246831B1 (en) | Preparation method of azithromycin dihydrate | |
CN115505051A (en) | Method for refining sugammadex sodium | |
CN109293722B (en) | Azithromycin related substance and preparation method thereof | |
WO2000032203A9 (en) | Ethanolate of azithromycin, process for manufacture, and pharmaceutical compositions thereof | |
CN106008614A (en) | Preparation method of high-purity aminosaccharides | |
CN113817005A (en) | Azithromycin related substance and synthesis method thereof | |
CN111635402B (en) | Separation and purification method of pyrroloquinoline quinone | |
CN112159445B (en) | Purification method and preparation method of beta-nicotinamide mononucleotide | |
CN111533771A (en) | Gamithromycin related substance and synthesis and separation method thereof | |
CN107033114B (en) | Method for separating and purifying dihydromyricetin | |
CN110563782B (en) | Gentamicin C 1a Purification method of (2) | |
CN102190691B (en) | Method for preparing high-purity 4'-epi-daunorubicin | |
EP3502121A1 (en) | Polymyxin b sulphate crystal and preparation method therefor | |
CN108059603B (en) | Refining process of Voglibose impurity N-methyl Jinggang enzyme alcohol amine | |
CN107739307B (en) | Method for purifying protocatechuic acid by using dilute alkali solution extraction-solid phase extraction column | |
CN112194693A (en) | Separation and purification method of doramectin | |
CN104926926B (en) | A kind of refining methd of enramycin | |
CN110655544A (en) | Method for separating, preparing and purifying gamithromycin related substances | |
KR102441251B1 (en) | Method for removing residual solvents from vancomycin | |
CN114276293B (en) | Preparation and purification method of methyl lotus plumule perchlorate | |
CN113698289B (en) | Method for preparing shikimic acid from ginkgo leaf extraction waste liquid | |
CN116768910B (en) | Refining method of rifabutin | |
CN114181270B (en) | Canagliflozin impurity, preparation method and removal method |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |