CN112480024A - Method for producing trans isomer of aminothiazoly loximate - Google Patents
Method for producing trans isomer of aminothiazoly loximate Download PDFInfo
- Publication number
- CN112480024A CN112480024A CN202011442011.7A CN202011442011A CN112480024A CN 112480024 A CN112480024 A CN 112480024A CN 202011442011 A CN202011442011 A CN 202011442011A CN 112480024 A CN112480024 A CN 112480024A
- Authority
- CN
- China
- Prior art keywords
- aminothiazoly loximate
- trans
- isomer
- loximate
- aminothiazoly
- 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
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 title claims abstract description 43
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 19
- 238000010992 reflux Methods 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 15
- 238000007670 refining Methods 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000020477 pH reduction Effects 0.000 abstract description 3
- 239000012065 filter cake Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 230000001276 controlling effect Effects 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- NLARCUDOUOQRPB-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- -1 methoxyimino Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for producing a trans-isomer of aminothiazoly loximate, belonging to the technical field of organic synthesis. The invention firstly dissolves the aminothiazoly loximate in acid for reflux reaction, then adds alkali for neutralization reaction after the reflux reaction is finished, and finally uses alcohol for refining and reflux to obtain the trans-isomer of the aminothiazoly loximate. The invention directly obtains the pure product of the trans-isomer of the aminothiazoly loximate after acidification, reflux reaction, neutralization and refining. Compared with the prior art, the method has the advantages of simple reaction process, mild reaction conditions, low cost and high purity of the obtained trans-isomer of the aminothiazoly loximate.
Description
Technical Field
The invention relates to a method for producing a trans-isomer of aminothiazoly loximate, belonging to the technical field of organic synthesis.
Background
The aminothiazoly loximate, namely 2- (2-amino-4-thiazolyl) -2-methoxyimino acetic acid (cis), is an important medical intermediate for synthesizing cephalosporin drugs. However, trans-isomer of the aminothiazoly loximate is easy to generate during the production and storage processes, and the trans-isomer of the aminothiazoly loximate is a main impurity of third-generation and fourth-generation cephalosporin medicaments. The trans isomer of aminothiazoly loximate, namely 2- (2-amino-4-thiazolyl) -2-methoxyimino acetic acid (trans), has the structural formula:
chinese patent CN 108707123A discloses a method for preparing and purifying a trans-isomer of aminothiazoly loximate, belonging to the technical field of organic synthesis. Comprises the following steps of (1) acylation reaction: dissolving aminothiazoly loximate in a solvent, introducing hydrochloric acid gas, adding N-N dimethylformamide, stirring, adding an acylation reagent, and carrying out an acylation reaction to obtain acyl chloride hydrochloride; (2) and (3) neutralization reaction: dissolving acyl chloride hydrochloride in water, adding alkali to perform a neutralization reaction to obtain sodium salt of the ainothiazoly loximate chloride; (3) and (3) acidification process: dissolving sodium salt of the amino-thiaximic acid acyl chloride in a solvent, and adding acid into a reaction solution to obtain the trans-isomer of the amino-thiaximic acid. The method has high yield and purity and simple operation; the main product is solid, is easy to separate and purify and does not need chromatographic separation; the crystallization refining method can be used for separating the trans isomers of the aminothiazoly loximate and the aminothiazoly loximate to obtain the pure products of the two, and the purity of the product can reach 99.79 percent. The yield can reach 48.4%. Although the trans-isomer of the aminothiazoly loximate is prepared by adopting a chemical synthesis method, the reaction process is complicated.
At present, a method for producing the trans-isomer of aminothiazoly loximate with simple process and low cost is needed to be provided.
Disclosure of Invention
The invention aims to provide a method for producing the trans-isomer of the ainothiazoly loximate, which has simple synthesis process and low cost, and the obtained trans-isomer of the ainothiazoly loximate has high purity.
The method for producing the trans-isomer of the ainothiazoly loximate comprises the steps of dissolving the ainothiazoly loximate in acid, and carrying out reflux reaction; adding alkali to carry out neutralization reaction after the reaction is finished, and controlling the pH value; and finally refining and refluxing the mixture by using alcohol to obtain the trans-isomer of the aminothiazoly loximate.
The acid is one or more of hydrochloric acid and sulfuric acid.
The mass ratio of the aminothiazoly loximate to the acid is 1: 5-7.
The reflux reaction temperature is 50-70 ℃, and the reflux reaction time is 22-26 h.
The alkali is sodium carbonate or sodium hydroxide.
The neutralization reaction temperature is 30-50 ℃.
Controlling the pH value to be 2-3.
The alcohol is one or more of methanol or ethanol.
The refining reflux temperature is 60-70 ℃, and the refining reflux time is 6-8 h.
More preferred steps are as follows:
dissolving the aminothiazoly loximate in acid, performing reflux reaction, and filtering; adding alkali into the filtrate to perform neutralization reaction, controlling the pH value, and preserving heat; and (3) cooling, suction filtering, refining and refluxing by using alcohol, suction filtering and drying to obtain the trans-isomer of the aminothiazoly loximate.
The drying temperature is 40-60 ℃, and the drying time is 3-5 h.
The reaction process of the invention is as follows:
under strong acid condition, the double bond of methoxyimino in cis-aminothiazoly loximate 1 is opened, nitrogen atom nucleophilically attacks hydrogen proton and changes into intermediate state 2, carbocation of intermediate state 2 is unstable, nitrogen atom of methoxyimino removes proton and carbocation to generate double bond and changes into intermediate state 3, and the intermediate state 3 is alkali-regulated and changes into trans-aminothiazoly loximate. The process utilizes the characteristic that the thermodynamic stability of the trans-aminothiazoly loximate is higher than that of the cis-aminothiazoly loximate under the strong acid condition to convert the cis-aminothiazoly loximate into the trans-isomer of the aminothiazoly loximate.
The invention has the following beneficial effects:
the invention firstly dissolves the aminothiazoly loximate in acid for reflux reaction, then adds alkali for neutralization reaction after the reflux reaction is finished, and finally uses alcohol for refining and reflux to obtain the trans-isomer of the aminothiazoly loximate. The invention directly obtains the pure product of the trans-isomer of the aminothiazoly loximate after acidification, reflux reaction, neutralization and refining. Compared with the prior art, the method has the advantages of simple reaction process, mild reaction conditions and low cost, and the obtained trans-isomer of the aminothiazoly loximate has high purity which is more than 99.3 percent. The trans-isomer of the aminothiazoly loximate can be used as a standard sample to monitor the quality of the medicines in the production and storage processes of the aminothiazoly loximate-related medicines, and can obtain the information of the quality conditions of the medicines in time.
Drawings
FIG. 1 is a gas chromatogram of the trans isomer of aminothiazoly loximate of example 1.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
Adding 100g of aminothiazoly loximate and 500mL of sulfuric acid into a 1000mL three-necked bottle, controlling the temperature to be 55-60 ℃, refluxing for 26h, cooling and filtering, heating the filtrate to 30-35 ℃, adjusting the pH value with a sodium hydroxide solution to perform a neutralization reaction, controlling the pH value to be 2-3, preserving the temperature for 1h, cooling and filtering, slightly drying the filter cake, then placing the filter cake into the 1000mL three-necked bottle, adding 5 times of ethanol by mass, heating to 60-65 ℃, refluxing for 8h, cooling and filtering, and drying the filter cake for 4h at 50 ℃ in an oven to obtain 45.6g of a product with the yield of 45.6%. The product is the trans-isomer of aminothiazoly loximate, and the HPLC purity is 99.30%. Peak 3 is the product peak of the trans isomer of aminothiazoly loximate.
Example 2
Adding 100g of aminothiazoly loximate and 500mL of hydrochloric acid into a 1000mL three-necked bottle, controlling the temperature to be 50-55 ℃, refluxing for 26h, cooling and filtering, heating the filtrate to 30-35 ℃, adjusting the pH value with a sodium hydroxide solution to perform a neutralization reaction, controlling the pH value to be 2-3, preserving the temperature for 1h, cooling and filtering, slightly drying the filter cake, then placing the filter cake into the 1000mL three-necked bottle, adding 5 times of ethanol by mass, heating to 60-65 ℃ to reflux for 8h, cooling and filtering, and drying the filter cake for 4h at 50 ℃ in an oven to obtain 46.2g of a product with the yield of 46.2%. The product is the trans-isomer of aminothiazoly loximate, and the HPLC purity is 99.35%.
Example 3
Adding 100g of aminothiazoly loximate and 700mL of hydrochloric acid into a 1000mL three-necked bottle, controlling the temperature to be 65-70 ℃, refluxing for 24h, cooling and filtering, heating the filtrate to 40-45 ℃, adjusting the pH value with a sodium hydroxide solution to perform a neutralization reaction, controlling the pH value to be 2-3, preserving the temperature for 1h, cooling and filtering, slightly drying the filter cake, then placing the filter cake into a 1000mL three-necked bottle, adding 5 times of methanol and ethanol (1:1v/v) in mass, heating to 60-65 ℃, refluxing for 6h, cooling and filtering, and drying the filter cake for 4h at 50 ℃ in an oven to obtain 46.6g of a product with the yield of 46.6%. The product is the trans-isomer of aminothiazoly loximate with an HPLC purity of 99.37%.
Example 4
Adding 100g of aminothiazoly loximate and 600mL of hydrochloric acid into a 1000mL three-necked bottle, controlling the temperature to be 50-55 ℃, refluxing for 24h, cooling and filtering, heating the filtrate to 30-35 ℃ to adjust the pH value by using a sodium hydroxide solution for neutralization reaction, controlling the pH value to be 2-3, keeping the temperature for 1h, cooling and filtering, slightly drying the filter cake, then placing the filter cake into a 1000mL three-necked bottle, adding 5 times of methanol by mass, heating to 65-70 ℃ to reflux for 7h, cooling and filtering, and drying the filter cake for 4h at 50 ℃ by using an oven to obtain 48.6g of a product with the yield of 48.6%. The product is the trans-isomer of aminothiazoly loximate, and the HPLC purity is 99.60%.
Example 5
100g of aminothiazoly loximate and 600mL of hydrochloric acid are added into a 1000mL three-neck flask, the temperature is controlled to be 65-70 ℃, reflux is carried out for 24 hours, and temperature reduction and filtration are carried out. Heating the filtrate to 45-50 ℃, adjusting the pH value with a sodium hydroxide solution to perform a neutralization reaction, controlling the pH value to be 2-3, keeping the temperature for 1h, cooling and filtering, slightly airing the filter cake, putting the filter cake into a 1000mL three-necked bottle, adding 5 times of methanol, heating to 65-70 ℃ to perform reflux for 7h, cooling and filtering, and drying the filter cake with an oven at 50 ℃ for 4h to obtain 50g of a product with the yield of 50%. The product is the trans-isomer of aminothiazoly loximate with HPLC purity of 99.70%.
Claims (10)
1. A method for producing the trans isomer of aminothiazoly loximate characterized by: dissolving the aminothiazoly loximate in acid, and carrying out reflux reaction; adding alkali to carry out neutralization reaction after the reaction is finished, and controlling the pH value; and finally refining and refluxing the mixture by using alcohol to obtain the trans-isomer of the aminothiazoly loximate.
2. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: the acid is one or more of hydrochloric acid and sulfuric acid.
3. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: the mass ratio of the aminothiazoly loximate to the acid is 1: 5-7.
4. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: the reflux reaction temperature is 50-70 ℃, and the reflux reaction time is 22-26 h.
5. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: the alkali is sodium carbonate or sodium hydroxide.
6. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: the neutralization reaction temperature is 30-50 ℃.
7. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: controlling the pH value to be 2-3.
8. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: the alcohol is one or more of methanol or ethanol.
9. The method for producing the trans isomer of aminothiazoly loximate according to claim 1, characterized in that: the refining reflux temperature is 60-70 deg.C, and the refining reflux time is 6-8 h.
10. A method for producing a trans isomer of aminothiazoly loximate according to any one of claims 1 to 9, characterized in that: dissolving the aminothiazoly loximate in acid, performing reflux reaction, and filtering; adding alkali into the filtrate to perform neutralization reaction, controlling the pH value, and preserving heat; and (3) cooling, suction filtering, refining and refluxing by using alcohol, suction filtering and drying to obtain the trans-isomer of the aminothiazoly loximate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011442011.7A CN112480024A (en) | 2020-12-11 | 2020-12-11 | Method for producing trans isomer of aminothiazoly loximate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011442011.7A CN112480024A (en) | 2020-12-11 | 2020-12-11 | Method for producing trans isomer of aminothiazoly loximate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112480024A true CN112480024A (en) | 2021-03-12 |
Family
ID=74941137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011442011.7A Pending CN112480024A (en) | 2020-12-11 | 2020-12-11 | Method for producing trans isomer of aminothiazoly loximate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112480024A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1576625A (en) * | 1976-04-12 | 1980-10-08 | Fujisawa Pharmaceutical Co | Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof |
| US4550105A (en) * | 1980-12-05 | 1985-10-29 | Takeda Chemical Industries, Ltd. | 1-Sulfo-2-oxoazetidine derivatives and their production |
| CN1793115A (en) * | 2005-11-18 | 2006-06-28 | 上海同纳环保科技有限公司 | Tech. for synthesizing high productivity oxime kresoxim |
| CN104529818A (en) * | 2014-12-16 | 2015-04-22 | 江苏耕耘化学有限公司 | Method for preparing (E)-2-(2-substituted phenyl)-2-methoxyimino acetic acid derivative |
| CN108707123A (en) * | 2018-07-19 | 2018-10-26 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method and purification process of ainothiazoly loximate transisomer |
| CN110845358A (en) * | 2018-08-20 | 2020-02-28 | 南通泰禾化工股份有限公司 | Preparation method of (E) -2- (2-tolyl) -2-methoxyimino methyl acetate |
-
2020
- 2020-12-11 CN CN202011442011.7A patent/CN112480024A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1576625A (en) * | 1976-04-12 | 1980-10-08 | Fujisawa Pharmaceutical Co | Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof |
| US4550105A (en) * | 1980-12-05 | 1985-10-29 | Takeda Chemical Industries, Ltd. | 1-Sulfo-2-oxoazetidine derivatives and their production |
| CN1793115A (en) * | 2005-11-18 | 2006-06-28 | 上海同纳环保科技有限公司 | Tech. for synthesizing high productivity oxime kresoxim |
| CN104529818A (en) * | 2014-12-16 | 2015-04-22 | 江苏耕耘化学有限公司 | Method for preparing (E)-2-(2-substituted phenyl)-2-methoxyimino acetic acid derivative |
| CN108707123A (en) * | 2018-07-19 | 2018-10-26 | 河北合佳医药科技集团股份有限公司 | A kind of preparation method and purification process of ainothiazoly loximate transisomer |
| CN110845358A (en) * | 2018-08-20 | 2020-02-28 | 南通泰禾化工股份有限公司 | Preparation method of (E) -2- (2-tolyl) -2-methoxyimino methyl acetate |
Non-Patent Citations (1)
| Title |
|---|
| MARTIN MANDEL，等: "New Synthesis of Oxime-type Beta-lactam Antiobiotics", 《COLLECT. CZECH. CHEM. COMMUN.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
| CN109734656B (en) | Preparation method of nitrendipine | |
| CN116751136A (en) | Novel preparation method of oxo-pyridine compound and key intermediate | |
| CN112480024A (en) | Method for producing trans isomer of aminothiazoly loximate | |
| JP2005506969A (en) | Novel modification of trometamol salt of R-thioctic acid and its production | |
| CN112010805B (en) | Refining method of fasudil hydrochloride | |
| CN115504864A (en) | Method for obtaining high-purity cannabidiol from industrial cannabis sativa | |
| CN111100121B (en) | Purification method of berberine or hydrochloride thereof | |
| CN113004281A (en) | Preparation method of entecavir intermediate | |
| US6197955B1 (en) | Production of staurosporine derivative using acid isomerization | |
| CN106187864A (en) | A kind of method being prepared high-purity bupivacaine alkali by bupivacaine hydrochloride | |
| CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
| CN111302996A (en) | Preparation method of high-chiral-purity chloromalastine fumarate | |
| CN113024484B (en) | Method for purifying and preparing high-purity promoter CZ and application thereof | |
| CN114149360B (en) | Preparation method of high-purity nitrendipine bulk drug | |
| CN116768910B (en) | Refining method of rifabutin | |
| CN114213343B (en) | Preparation and purification methods of celecoxib intermediate | |
| CN114213260B (en) | Preparation method of prionamine iodide | |
| CN110903230B (en) | Industrial preparation method of pramipentane sulfate | |
| CN107365299B (en) | Preparation method of dabigatran etexilate and intermediate thereof | |
| CN109422679B (en) | Purification of bedaquiline and preparation method of stable crystal form | |
| CN108727351B (en) | Refining method of prucalopride | |
| KR20170123132A (en) | Process for Preparing Treprostinil | |
| KR20040044636A (en) | Method for purifing of ethyl 4-(1-imidazoleylmethyl)cinnamate |
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 |
Application publication date: 20210312 |
|
| RJ01 | Rejection of invention patent application after publication |