CN112094244A - Synthesis method of 1-methyl-5-mercapto tetrazole - Google Patents
Synthesis method of 1-methyl-5-mercapto tetrazole Download PDFInfo
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- CN112094244A CN112094244A CN202010988623.XA CN202010988623A CN112094244A CN 112094244 A CN112094244 A CN 112094244A CN 202010988623 A CN202010988623 A CN 202010988623A CN 112094244 A CN112094244 A CN 112094244A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Abstract
The invention relates to a synthesis method of 1-methyl-5-mercapto tetrazole, which comprises the following steps of (1) taking sodium methylamino dithio carboxylate and sodium azide as reaction raw materials, taking water as a reaction solvent, taking an alkali solution as a catalyst, carrying out reflux reaction, neutralizing the reaction liquid after the reaction to pH =6-7 by protonic acid, and filtering to obtain a crude product of 1-methyl-5-mercapto tetrazole; (2) and (2) recrystallizing the 1-methyl-5-mercaptotetrazole crude product obtained in the step (1) through a recrystallization solution to obtain a 1-methyl-5-mercaptotetrazole finished product, wherein the recrystallization solution is a mixed solution of toluene and water. The synthesis method has high yield, and the prepared 1-methyl-5-mercapto tetrazole has high purity.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 1-methyl-5-mercapto tetrazole.
Background
The 1-methyl-5-mercapto tetrazole is also called methyl mercapto tetrazole, is an important raw material of a plurality of third, fourth and fifth generations of cephalosporin antibiotics, is mainly used as an intermediate of more than ten cephalosporin drugs such as cefoperazone sodium, cefamandole, cefmenoxime hydrochloride, cefmetazole, cefotetan, cefpiramide and the like, and the purity of the product directly determines the pharmaceutical activity of the cephalosporin drugs.
At present, the synthesis of 1-methyl-5-mercapto tetrazole mainly uses methyl isothiocyanate as a raw material to react with sodium azide to generate a target product: zhang Jianyu et al propose to take methyl isothiocyanate and sodium azide as raw materials, ethanol as a solvent, react for 3 hours at 75 ℃ to obtain a crude product, after the reaction is finished, hydrochloric acid is used for adjusting the pH value to acidity, and ethyl ether is used for extracting, drying and concentrating the crude product, wherein the total yield of the reaction is 40%. ② patent CN201010115803.3 proposes adding sodium azide into deionized water under stirring, adding a small amount of phase transfer catalyst, dripping methyl isothiocyanate at 80 ℃, and keeping the temperature to react until the reaction is finished. After the reaction is finished, concentrating to half volume, cooling to-5 ℃, adding hydrochloric acid to adjust the pH value to acidity, and crystallizing to obtain a crude product. Adriana et al showed that methyl isothiocyanate was reacted with sodium azide in water as solvent for 6 hours under reflux, and after the reaction was completed, ether was used for extraction twice, pH was adjusted to 3 with hydrochloric acid, and the product was obtained by extraction and concentration with a yield of 28%.
The existing preparation method of 1-methyl-5-mercapto tetrazole has low yield, and aiming at the defects of the prior art, a synthesis process which has high product yield and high product purity and is suitable for industrial production needs to be developed.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of 1-methyl-5-mercapto tetrazole, the synthesis method has high yield, and the prepared 1-methyl-5-mercapto tetrazole has high purity.
In order to achieve the purpose, the technical scheme of the invention comprises the following steps:
(1) taking sodium methylamino dithio carboxylate and sodium azide as reaction raw materials, taking water as a reaction solvent and inorganic base as a catalyst, carrying out reflux reaction, neutralizing the reaction solution after the reaction is finished by protonic acid until the pH value is 6-7, and filtering to obtain a crude product of 1-methyl-5-mercapto tetrazole;
(2) and (2) recrystallizing the 1-methyl-5-mercaptotetrazole crude product obtained in the step (1) through a recrystallization solution to obtain a 1-methyl-5-mercaptotetrazole finished product, wherein the recrystallization solution is a mixed solution of toluene and water.
Further, in the step (1), the molar ratio of the sodium methylamino dithiocarboxylate to the sodium azide is 1:1-1.2: 1.
Further, in the step (1), the mass ratio of the reaction solvent to the sodium methylaminodithiocarboxylate is 6:1 to 8: 1.
Further, in the step (1), the protonic acid is hydrochloric acid or sulfuric acid.
Further, in the step (1), the protonic acid is hydrochloric acid with a mass fraction of 36% or sulfuric acid with a mass fraction of 50%.
Further, in the step (1), the reflux reaction is carried out for 14-16h at the temperature of 85-95 ℃.
Further, in the step (1), after mixing the sodium methylamino dithio carboxylate and the reaction solvent water, sequentially adding the catalyst and the sodium azide under stirring, carrying out reflux reaction, after the reaction is completed, cooling to below 10 ℃, carrying out suction filtration, heating the filtrate obtained by suction filtration to 30-40 ℃, stirring for 30min, neutralizing the reaction solution after the reaction is completed with protonic acid until the pH value is 6-7, stirring for 30min, cooling to below 10 ℃, carrying out suction filtration, and obtaining the filter cake which is the crude product of 1-methyl-5-mercapto tetrazole.
Further, in the step (1), the catalyst is sodium hydroxide or sodium carbonate solution.
Further, the mass fraction of the catalyst is 30-50%.
Further, in the step (2),
the volume ratio of the 1-methyl-5-mercapto tetrazole crude product to the recrystallization solution is 1:4-1: 5.
Further, in the step (2), the mass fraction of toluene in the recrystallization solution is 65% -75%, and the balance is water.
The reaction process of the present invention is as follows.
The invention has the following positive effects:
the method takes the methylamino sodium dithio-carboxylate and the sodium azide as raw materials, takes water as a reaction solvent, generates a target product through reflux reaction under the catalysis of inorganic base, obtains a crude product through neutralization and separation of a system, is mild and controllable in reaction process, is a water-phase reaction in the reaction process, is green and environment-friendly, accords with the concept of sustainable development, has high reaction activity and improved product conversion rate by taking the methylamino sodium dithio-carboxylate as the reaction raw material compared with the traditional reaction, avoids the problem of difficult biodegradation caused by the use of organic bases such as triethylamine and the like by using the inorganic base and the protonic acid in the reaction process, generates inorganic salt, and has simple and easy post-treatment. The crude product is recrystallized by using a toluene-water two-phase solvent, organic impurities and inorganic impurities can be removed simultaneously, the purification efficiency is high, the purity of the obtained product is high, the yield is high, the reaction process is safer, and the method is suitable for industrial production.
Drawings
FIG. 11 is HPLC chromatogram of methyl-5-mercapto tetrazole standard sample;
FIG. 2 is HPLC chromatogram of 1-methyl-5-mercapto tetrazole synthesized in example 1 of the present invention.
Detailed description of the preferred embodiments
Example 1
Sodium methyldithiocarboxylate (39.8g) and reaction solvent water (239.2g) were sequentially added to a 500mL four-necked flask, stirring was started, 41.13g of a 30% by mass aqueous solution of sodium hydroxide was added to the four-necked flask, 20g of sodium azide was then added to the reaction system, and the temperature was raised to 90 ℃ to conduct a reflux reaction for 15 hours. Cooling to 9 deg.C after sampling and detecting, vacuum filtering, heating filtrate to 35 deg.C, stirring for 30min, neutralizing with 62.5g of hydrochloric acid with the mass concentration of 36% until the pH value is 6, stirring for 30min, cooling to 8 ℃, performing suction filtration, wherein the filter cake is a 1-methyl-5-mercaptotetrazole crude product, dissolving the obtained 1-methyl-5-mercaptotetrazole crude product in a recrystallization solution with the volume of 4 times of that of the crude product, performing recrystallization, wherein the recrystallization solution is toluene with the mass fraction of 65% to 35% water, separating and drying to obtain a finished product (33.4g), the product yield is 93.5%, and the nuclear magnetic spectrum of the product is shown in figure 1, wherein 1H-NMR (400MHz, D2O): the HPLC spectrum of the product obtained was consistent with that of the standard sample, while the HPLC spectrum of the product obtained was consistent with that of the standard sample, 4.79(s,1H, -SH),3.76(s,3H, -CH 3).
Example 2
41.9g of sodium methyldithiocarboxylate and 293g of water are sequentially added into a 500mL four-neck bottle, stirring is started, 32.48g of sodium hydroxide aqueous solution with the mass fraction of 40% is added into the four-neck bottle, 20g of sodium azide is added into a reaction system, and the temperature is raised to 85 ℃ for heat preservation reaction for 16 hours. Cooling to 10 ℃ after sampling and detection are qualified, carrying out suction filtration, heating filtrate obtained by suction filtration to 30 ℃, stirring for 30min, neutralizing with 65.4g of hydrochloric acid with the mass concentration of 36% until the pH value is 7, stirring for 30min, cooling to 10 ℃, carrying out suction filtration to obtain a 1-methyl-5-mercaptotetrazole crude product, dissolving the obtained 1-methyl-5-mercaptotetrazole crude product in a recrystallization solution with the volume of 5 times of that of the crude product for recrystallization, carrying out recrystallization on the recrystallization solution with the mass fraction of 70% toluene and 30% water, separating and drying a crystallized product after the recrystallization is finished, obtaining a finished product 33.26g, wherein the product yield is 93.2%, and the HPLC spectrogram of the obtained product is consistent with that of a standard sample.
Example 3
39.8g of sodium methyldithiocarboxylate and 319g of water are sequentially added into a 500mL four-neck bottle, stirring is started, 24.68g of sodium hydroxide aqueous solution with the mass fraction of 50% is added into the four-neck bottle, 20g of sodium azide is added into a reaction system, and the temperature is raised to 95 ℃ for reaction under heat preservation for 14 hours. Cooling to 7 ℃ after sampling and detection are qualified, carrying out suction filtration, heating the filtrate obtained by suction filtration to 40 ℃, stirring for 30min, neutralizing with 62.5g of hydrochloric acid with the mass concentration of 36% until the pH value is 7, stirring for 30min, cooling to 9 ℃, carrying out suction filtration, wherein the filter cake is a 1-methyl-5-mercaptotetrazole crude product, dissolving the 1-methyl-5-mercaptotetrazole crude product in a recrystallization solution with the volume of 5 times that of the crude product for recrystallization, separating and drying the recrystallization solution which is 75% toluene-25% by mass fraction in the embodiment to obtain 33.4g of a finished product, wherein the yield of the product is 93.6%, and the HPLC spectrogram of the obtained product is consistent with that of a standard sample.
Example 4
43.7g of methylamino dithio carboxylic acid sodium and 262g of water are sequentially added into a 5000L four-neck bottle, stirring is started, 45.17g of sodium hydroxide aqueous solution with the mass fraction of 30 percent is added into the four-neck bottle, 20g of sodium azide is added into a reaction system, and the temperature is raised to 87 ℃ for heat preservation reaction for 15 hours. Cooling to 8 ℃ after sampling and detection are qualified, carrying out suction filtration, heating the filtrate to 34 ℃, stirring for 30min, neutralizing with 68.66g of hydrochloric acid with the mass concentration of 36% until the pH value is 6, stirring for 30min, cooling to 9 ℃, carrying out suction filtration, dissolving the filter cake in a recrystallization solution with the volume of 4.5 times of that of the filtrate, wherein the recrystallization solution in the embodiment is 75-25% of toluene by mass fraction, separating and drying to obtain 33.26g of a finished product, the product yield is 93.2%, and the HPLC spectrogram of the obtained product is consistent with that of a standard sample.
Example 5
Adding 45.6g of methylamino dithio carboxylic acid sodium and 274g of water into a 5000L four-mouth bottle in sequence, starting stirring, adding 46.8g of sodium carbonate aqueous solution with the mass fraction of 40% into the four-mouth bottle, adding 20g of sodium azide into a reaction system, heating to 92 ℃, and carrying out heat preservation reaction for 16 hours. Cooling to 9 ℃ after sampling detection is qualified, carrying out suction filtration, heating the filtrate to 37 ℃, stirring for 30min, neutralizing with 69.3g of sulfuric acid with the mass concentration of 50% until the pH value is 6, stirring for 30min, cooling to below 10 ℃, carrying out suction filtration, recrystallizing the filter cake with water with the mass fraction of 75% to 25% and the volume of 5 times that of the filter cake, separating and drying to obtain 33.22g of a finished product, wherein the product yield is 93.1%, and the HPLC spectrogram of the obtained product is consistent with that of a standard sample.
Example 6
47.6g of sodium methyldithiocarboxylate and 286g of water are sequentially added into a 5000L four-mouth bottle, stirring is started, 65.18g of sodium carbonate aqueous solution with the mass fraction of 30 percent is added into the four-mouth bottle, 20g of sodium azide is added into a reaction system, and the temperature is raised to 86 ℃ for reaction under the condition of heat preservation for 14 hours. Cooling to below 10 ℃ after sampling and detection are qualified, carrying out suction filtration, heating the filtrate obtained by suction filtration to 38 ℃, stirring for 30min, neutralizing with 72.3g of sulfuric acid with the mass concentration of 50% until the pH value is 6, stirring for 30min, cooling to 10 ℃, carrying out suction filtration, recrystallizing the filter cake with water with the mass fraction of 65% to 35% in a volume of 4 times, separating and drying to obtain 33.44g of a finished product, wherein the product yield is 93.7%, and the HPLC spectrogram of the obtained product is consistent with that of a standard sample.
Example 7
41.9g of sodium methyldithiocarboxylate and 293g of water are sequentially added into a 5000L four-mouth bottle, stirring is started, 68.8g of sodium carbonate aqueous solution with the mass fraction of 50 percent is added into the four-mouth bottle, 20g of sodium azide is added into a reaction system, and the temperature is raised to 85 ℃ for heat preservation reaction for 14 hours. Cooling to 8 ℃ after sampling and detection are qualified, carrying out suction filtration, heating the filtrate obtained by suction filtration to 31 ℃, stirring for 30min, neutralizing with 65.4g of hydrochloric acid with the mass fraction of 36% until the pH value is 7, stirring for 30min, cooling to 10 ℃, carrying out suction filtration, fully dissolving the filter cake with a recrystallization solution of which the volume is 5 times that of the filter cake, carrying out recrystallization with 70% toluene and 30% water in mass fraction, separating and drying to obtain 33.26g of a finished product, wherein the product yield is 93.2%, and the HPLC spectrogram of the obtained product is consistent with that of a standard sample.
In the invention, a standard sample spectrogram is shown in figure 1, and the acquisition method comprises the following steps: HPLC analysis of commercially available reagent grade 1-methyl-5-mercaptotetrazole.
Performing liquid chromatography spectrogram analysis on the solid finished product 1-methyl-5-mercaptotetrazole obtained in the example 1, wherein the liquid phase conditions of the 1-methyl-5-mercaptotetrazole are as follows:
the instrument name: wufeng liquid phase
A chromatographic column: dimamei C18 column, 5um, 250nm x 4.6mm liquid chromatography column or other equivalent chromatography columns
A detector: UV detector
Mobile phase: 0.1% phosphoric acid aqueous solution: acetonitrile 70%: 30 percent of
Column temperature: 30 deg.C
Flow rate: 1ml/min
Detection wavelength: 210nm
Sample introduction amount: 20uL
The HPLC spectrum of the 1-methyl-5-mercaptotetrazole obtained in example 1 is shown in fig. 2, and it can be known from comparison between fig. 1 and fig. 2 that the HPLC spectrum of the 1-methyl-5-mercaptotetrazole prepared by the invention is consistent with the HPLC spectrum of a standard sample.
The method has the advantages of high purification efficiency, high purity of the obtained product, high yield, safer reaction process and suitability for industrial production.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A method for synthesizing 1-methyl-5-mercapto tetrazole is characterized by comprising the following steps: comprises the following steps of (a) carrying out,
(1) taking sodium methylamino dithio carboxylate and sodium azide as reaction raw materials, taking water as a reaction solvent and taking an alkali solution as a catalyst, carrying out reflux reaction, neutralizing the reaction solution after the reaction is finished by protonic acid until the pH is =6-7, and filtering to obtain a crude product of 1-methyl-5-mercaptotetrazole;
(2) and (2) recrystallizing the 1-methyl-5-mercaptotetrazole crude product obtained in the step (1) through a recrystallization solution to obtain a 1-methyl-5-mercaptotetrazole finished product, wherein the recrystallization solution is a mixed solution of toluene and water.
2. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1, wherein the method comprises the following steps: in the step (1), the molar ratio of the methylamino dithiocarboxylic acid sodium to the sodium azide is 1:1-1.2: 1.
3. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1, wherein the method comprises the following steps: in the step (1), the mass ratio of the reaction solvent to the sodium methylamino dithiocarboxylate is 6:1-8: 1.
4. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1, wherein the method comprises the following steps: in the step (1), the protonic acid is hydrochloric acid or sulfuric acid.
5. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1, wherein the method comprises the following steps: in the step (1), the reflux reaction is carried out for 14-16h at the temperature of 85-95 ℃.
6. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1 or 5, wherein the method comprises the following steps: in the step (1), after mixing the sodium methylamino dithio carboxylate and the reaction solvent water, sequentially adding a catalyst and sodium azide under stirring, carrying out reflux reaction, after the reaction is completed, cooling to below 10 ℃, then carrying out suction filtration, heating the filtrate obtained by suction filtration to 30-40 ℃, stirring for 30min, neutralizing the reaction solution after the reaction is completed with protonic acid until the pH =6-7, stirring for 30min, cooling to below 10 ℃, and carrying out suction filtration to obtain a filter cake which is a crude product of 1-methyl-5-mercaptotetrazole.
7. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1, wherein the method comprises the following steps: in the step (1), the catalyst is sodium hydroxide or sodium carbonate solution, and the molar ratio of the catalyst to the methylamino sodium dithiocarboxylate is 1: 1.
8. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 7, wherein the method comprises the following steps: the mass fraction of the catalyst is 30-50%.
9. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1, wherein the method comprises the following steps: in the step (2),
the volume ratio of the 1-methyl-5-mercapto tetrazole crude product to the recrystallization solution is 1:4-1: 5.
10. The method for synthesizing 1-methyl-5-mercapto tetrazole according to claim 1, wherein the method comprises the following steps: in the step (2), the mass fraction of toluene in the recrystallization solution is 65-75%, and the balance is water.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357829A (en) * | 2019-07-18 | 2019-10-22 | 山东金城柯瑞化学有限公司 | A kind of preparation method of 5- sulfydryl -1H- tetrazole compound |
| CN113866300A (en) * | 2021-09-26 | 2021-12-31 | 山东建筑大学 | Method for detecting sodium azide in medicine or intermediate thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86108880A (en) * | 1985-12-26 | 1987-07-22 | Fmc公司 | 1-aryl-4 substituting group-1,4-dihydro-5H-tetrazolium-5-ketone and sulfur analogs weedicide thereof |
| WO2003106436A1 (en) * | 2002-06-14 | 2003-12-24 | Bayer Cropscience Ag | Nematicidal tetrazole-containing trifluorobutenes |
| CN101367771A (en) * | 2008-10-07 | 2009-02-18 | 青岛科技大学 | Synthesis of 1-substituted-5-sulfhydryl-tetrazole compounds or its salt |
-
2020
- 2020-09-18 CN CN202010988623.XA patent/CN112094244A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86108880A (en) * | 1985-12-26 | 1987-07-22 | Fmc公司 | 1-aryl-4 substituting group-1,4-dihydro-5H-tetrazolium-5-ketone and sulfur analogs weedicide thereof |
| WO2003106436A1 (en) * | 2002-06-14 | 2003-12-24 | Bayer Cropscience Ag | Nematicidal tetrazole-containing trifluorobutenes |
| CN101367771A (en) * | 2008-10-07 | 2009-02-18 | 青岛科技大学 | Synthesis of 1-substituted-5-sulfhydryl-tetrazole compounds or its salt |
Non-Patent Citations (1)
| Title |
|---|
| E. LIPPMANN: "Darstellung und massenspektrometrische Fragmentierung von 1-Phenyl-5-mercaptotetrazol und im Phenylkern substituierten Derivaten", 《J. SIGNAL AM》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357829A (en) * | 2019-07-18 | 2019-10-22 | 山东金城柯瑞化学有限公司 | A kind of preparation method of 5- sulfydryl -1H- tetrazole compound |
| CN113866300A (en) * | 2021-09-26 | 2021-12-31 | 山东建筑大学 | Method for detecting sodium azide in medicine or intermediate thereof |
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Application publication date: 20201218 |