CN110563699A - Post-treatment purification method of fluoro pranoprazan intermediate - Google Patents
Post-treatment purification method of fluoro pranoprazan intermediate Download PDFInfo
- Publication number
- CN110563699A CN110563699A CN201910976051.0A CN201910976051A CN110563699A CN 110563699 A CN110563699 A CN 110563699A CN 201910976051 A CN201910976051 A CN 201910976051A CN 110563699 A CN110563699 A CN 110563699A
- Authority
- CN
- China
- Prior art keywords
- pranoprazan
- fluoro
- post
- solvent
- purification method
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention provides a post-treatment purification method for preparing a chemical drug of pinapranoprazan intermediate 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine compound for treating gastric ulcer, duodenal ulcer and reflux esophagitis; the invention provides a post-treatment purification method for producing 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine by reacting 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-formaldehyde with a methylamine methanol solution in the presence of an organic solvent and reducing the reaction product by a reducing agent, wherein the post-treatment purification method effectively reduces the content of impurities and improves the quality of a subsequent target product; the post-treatment purification method has the advantages of stable process, high yield, good quality, simple operation, continuous application of recovered solvent, less three wastes and low production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of chemical pharmacy, in particular to a post-treatment purification method of a fluoro pranoprazan intermediate.
Background
The preparation method of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine related to the prior literature comprises the following steps: the CN 104926790a application discloses a high purity vonoPrazan Fumarate compound and its intermediate, impurities and their preparation method and the synthesis method reported in patent WO2007026916 all use 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde as key intermediate, react with methylamine to obtain imine, then undergo reduction reaction with sodium borohydride, acidification with hydrochloric acid, alkalization, ethyl acetate extraction, brine washing, drying with anhydrous magnesium sulfate, concentrating to obtain the concentrated solution of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine. In patent WO2007026916, an alkaline silica gel column is used for separation and concentration to obtain the oily compound (I). In the preparation method of CN1O492679OA, sodium borohydride and N, N-dimethyl acetamide solution are used for reduction reaction in imine reduction, so that a large amount of waste water containing N, N-dimethyl acetamide is generated in the post-treatment process. The method disclosed in the patent has the disadvantages that the obtained 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine is all reported to be oily substances, and the recovered solvent is a mixed solvent, so that the solvent is difficult to recover and comprehensively utilize, and certain resource waste and environmental pollution are caused. And the post-treatment is complex, a large amount of saturated salt solution is needed for washing, so that the product yield is low, the production efficiency is low, the energy consumption is high, the three wastes are more, the production cost is high, and the industrial production is difficult to realize.
Disclosure of Invention
The invention provides a post-treatment purification method of a fluoro pranoprazan intermediate, which comprises the following three steps:
(1) Reacting 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-formaldehyde with methylamine, and reducing to prepare a reaction mixed solution of a fluoro pranoprazan intermediate;
(2) carrying out reduced pressure distillation on the reaction mixed liquid obtained in the step (1) to recover a solvent, alkalifying and dissociating, extracting with an organic solvent, and concentrating the organic phase under reduced pressure to obtain a crude product of the intermediate of the fluoro-pranoprazan;
(3) Recrystallizing the crude product of the fluoro Na pranoprazan intermediate obtained in the step (2) by using a mixed solvent, and drying to prepare a high-purity fluoro Na pranoprazan intermediate;
The pinapranoprazan intermediate is 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine.
The post-treatment purification method of the fluoro Na pranoprazan intermediate is characterized by comprising the following steps: the post-treatment method comprises the steps of distilling the reaction mixed liquor of the fluoro pranoprazan intermediate under reduced pressure to recover the solvent, dissociating the fluoro pranoprazan intermediate by using the aqueous solution of sodium carbonate in the concentrated solution, extracting by using a conventional solvent, and concentrating under reduced pressure by using an organic phase to obtain a crude product of the fluoro pranoprazan intermediate.
The post-treatment purification method of the fluoro Na pranoprazan intermediate is characterized in that the temperature of the reaction mixed liquid in the step (2) for recovering the solvent by reduced pressure distillation is controlled to be 40-50 ℃, and the vacuum degree is more than or equal to-0.08 MPa; the water solution of sodium carbonate is a saturated solution, and the pH value of the alkalized free sodium carbonate is 8-9; the solvent used is a conventional solvent dichloromethane, and the amount of the solvent used is 15-20 times (mass ratio) of the reactant 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde.
The post-treatment purification method of the fluoro pranoprazan intermediate is characterized in that after the extraction in the step (2) is finished, an organic phase is subjected to vacuum concentration, the temperature is controlled below 40 ℃, and the vacuum degree is more than or equal to-0.08 MPa, and the post-treatment purification method of the fluoro pranoprazan intermediate is characterized in that: the recrystallization solvent in the step (3) is a mixed solvent and consists of methanol and isopropyl ether; the mass ratio of the crude product of the fluoro pranoprazan intermediate to the mixed solvent to the activated carbon is 1: 4-6: 0.05 to 0.1; methanol: isopropyl ether ═ 1: 2-3;
The post-treatment purification method of the fluoro Na pranoprazan intermediate is characterized by comprising the following steps: and (3) after air is replaced by nitrogen, decoloring the crude product at the nitrogen pressure of more than or equal to 0.01Mpa at the temperature of 60-65 ℃, crystallizing and filtering at the temperature of 0-5 ℃, and keeping the temperature for crystallization for 0.5 hour.
A post-treatment purification method of a fluoro pranoprazan intermediate is characterized by comprising the following steps: the drying process in the step (3) is vacuum drying under the nitrogen and vacuum alternative exchange, the drying time is 3-4 hours, the drying temperature is 40-60 ℃, and the vacuum degree is more than or equal to-0.08 MPa.
the invention aims to provide a post-treatment purification method which has high purity, HPLC purity of more than 99.7 percent, single impurity of less than 0.1 percent, stable post-treatment purification method process, high yield, less three wastes and low production cost and is suitable for industrial production of 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine.
Compared with the prior art, the invention has the following beneficial effects:
the invention has the advantages that: the post-treatment purification method has the advantages of stable process, simple post-treatment, less three wastes, continuous and cyclic use of mother liquor, good product quality, high yield and low production cost, and is suitable for industrial production.
The invention is further illustrated by the following examples:
Detailed Description
The present invention is further described below with reference to examples.
Example 1
Step (1): 20g of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde and the appropriate amount of methanol as solvent were placed in a reaction flask equipped with a stirrer and a thermometer, and while stirring, the appropriate amount of methylamine methanol solution was slowly added thereto while controlling the temperature at about 20 ℃. Adding a metered reducing agent for reaction till the reaction is complete, and adjusting the pH value to 6 after the reaction is finished to prepare a reaction mixed solution of 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine.
step (2): and (2) adding the reaction mixed solution of the 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine prepared in the step (1) into a distillation reaction bottle, controlling the vacuum degree to be more than or equal to-0.08 Mpa and the temperature to be below 40-50 ℃, carrying out reduced pressure distillation to recover the solvent, cooling to room temperature after the distillation is finished, adjusting the pH to be 8 by using an aqueous solution of sodium carbonate, and extracting by using 300ml of dichloromethane for three times. And carrying out reduced pressure distillation on the organic phase to recover the solvent, controlling the vacuum degree to be more than or equal to-0.08 MPa and the temperature to be below 40 ℃ until no distillate exists, thus obtaining 22g of crude oil 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine.
and (3): adding 29.3g of methanol and 58.7g of isopropyl ether into 22g of the crude 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine obtained in the step (2), stirring, adding 1.1g of activated carbon, replacing air with nitrogen, heating to dissolve the mixture to 65 ℃, decoloring for 30 minutes, filtering, slowly cooling the filtrate to 5 ℃ under stirring, keeping the temperature for crystallization for 0.5 hour, filtering, washing with isopropyl ether, draining, discharging, drying the wet product under reduced pressure, replacing the dried product with small-flow nitrogen for 3 times, controlling the drying temperature to be 40 ℃, controlling the vacuum degree to be more than or equal to-0.08 MPa, and drying for 4 hours to obtain 17.3g of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine Refined methylamine, HPLC content 99.87%.
example 2
Step (1): same example procedure (1)
step (2): and (2) adding the reaction mixed solution of the 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine prepared in the step (1) into a distillation reaction bottle, controlling the vacuum degree to be more than or equal to-0.08 Mpa and the temperature to be below 40-50 ℃, carrying out reduced pressure distillation to recover the solvent, cooling to room temperature after the distillation is finished, adjusting the pH to be 9 by using an aqueous solution of sodium carbonate, and extracting by using 400ml of dichloromethane for three times. And carrying out reduced pressure distillation on the organic phase to recover the solvent, controlling the vacuum degree to be more than or equal to-0.08 MPa and the temperature to be below 40 ℃ until no distillate exists, thus obtaining 22.6g of crude 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine compound (I) of oily matter.
and (3): adding 33.9g of methanol and 101.7g of isopropyl ether into 22.6g of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine crude product obtained in the step (2), stirring, adding 2.3g of activated carbon, replacing air with nitrogen, heating to dissolve the mixture to 60 ℃, decoloring for 30 minutes, filtering, slowly cooling the filtrate to 0 ℃ under stirring, keeping the temperature for crystallization for 0.5 hour, filtering, washing with isopropyl ether, draining, drying the wet product under reduced pressure, replacing the wet product with small-flow nitrogen for 3 times in the drying process, controlling the drying temperature to be 40 ℃, controlling the vacuum degree to be more than or equal to-0.08 MPa, and drying for 4 hours to obtain 18.1g of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine crude product Refined methylamine, HPLC content 99.91%.
Example 3
step (1): same example procedure (1)
Step (2): and (2) adding the reaction mixed solution of the 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine prepared in the step (1) into a distillation reaction bottle, controlling the vacuum degree to be more than or equal to-0.08 Mpa and the temperature to be below 40-50 ℃, carrying out reduced pressure distillation to recover the solvent, cooling to room temperature after the distillation is finished, adjusting the pH to be 8.5 by using an aqueous solution of sodium carbonate, and extracting by using 350ml of dichloromethane for three times. And carrying out reduced pressure distillation on the organic phase to recover the solvent, controlling the vacuum degree to be more than or equal to-0.08 MPa and the temperature to be below 40 ℃ until no distillate exists, thus obtaining 22.7g of crude oil 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine.
And (3): adding 32.4g of methanol and 81.1g of isopropyl ether into 22.7g of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine crude product obtained in the step (2), stirring, adding 1.7g of activated carbon, replacing air with nitrogen, heating to dissolve the mixture to 63 ℃, decoloring for 30 minutes, filtering, slowly cooling the filtrate to 2 ℃ under stirring, keeping the temperature for crystallization for 0.5 hour, filtering, washing with isopropyl ether, draining, drying the wet product under reduced pressure, replacing the wet product with small-flow nitrogen for 3 times in the drying process, controlling the drying temperature to be 40 ℃, controlling the vacuum degree to be more than or equal to-0.08 MPa, and drying for 4 hours to obtain 18.2g of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine crude product Refined methylamine, HPLC content 99.89%.
Example 4
Step (1): same example procedure (1)
Step (2): and (2) adding the reaction mixed solution of the 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine prepared in the step (1) into a distillation reaction bottle, controlling the vacuum degree to be more than or equal to-0.08 Mpa and the temperature to be below 40-50 ℃, carrying out reduced pressure distillation to recover the solvent, cooling to room temperature after the distillation is finished, adjusting the pH to be 8.5 by using an aqueous solution of sodium carbonate, and extracting by using 400ml of dichloromethane for three times. And carrying out reduced pressure distillation on the organic phase to recover the solvent, controlling the vacuum degree to be more than or equal to-0.08 MPa and the temperature to be below 40 ℃ until no distillate exists, thus obtaining 23.1g of crude oil 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine.
And (3): adding 33g of methanol and 82.5g of isopropyl ether into 23.1g of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine crude product obtained in the step (2), adding 2.3g of activated carbon while stirring, replacing air with nitrogen, heating to dissolve the mixture to 65 ℃, decoloring for 30 minutes, filtering, slowly cooling the filtrate to 3 ℃ while stirring, keeping the temperature for crystallization for 0.5 hour, filtering, washing with isopropyl ether, draining, discharging, drying wet products under reduced pressure, replacing the dried products with small-flow nitrogen for 3 times while controlling the drying temperature to be 40 ℃, controlling the vacuum degree to be more than or equal to-0.08 MPa, and drying for 4 hours to obtain 18.0g of 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine crude product Refined methylamine, HPLC content 99.92%.
Claims (7)
1. A post-treatment purification method of a fluoro pranoprazan intermediate is characterized by comprising the following steps: the method comprises three steps:
(1) Reacting 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-formaldehyde with methylamine, and reducing to prepare a reaction mixed solution of a fluoro pranoprazan intermediate;
(2) Carrying out reduced pressure distillation on the reaction mixed liquid obtained in the step (1) to recover a solvent, alkalifying and dissociating, extracting with an organic solvent, and concentrating the organic phase under reduced pressure to obtain a crude product of the intermediate of the fluoro-pranoprazan;
(3) recrystallizing the crude product of the fluoro Na pranoprazan intermediate obtained in the step (2) by using a mixed solvent, and drying to prepare a high-purity fluoro Na pranoprazan intermediate;
The pinapranoprazan intermediate is 1- [5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonyl) -1H-pyrrole-3-yl ] -N-methyl methylamine.
2. The post-treatment purification method of the fluoro pranoprazan intermediate according to claim 1, which is characterized in that: the post-treatment method comprises the steps of distilling the reaction mixed liquor of the fluoro pranoprazan intermediate under reduced pressure to recover the solvent, dissociating the fluoro pranoprazan intermediate by using the aqueous solution of sodium carbonate in the concentrated solution, extracting by using a conventional solvent, and concentrating under reduced pressure by using an organic phase to obtain a crude product of the fluoro pranoprazan intermediate.
3. The post-treatment purification method of the fluoro Na pranoprazan intermediate according to claim 1 or 2, characterized in that the temperature of the reaction mixed solution in the step (2) for recovering the solvent by reduced pressure distillation is controlled between 40 ℃ and 50 ℃, and the vacuum degree is more than or equal to-0.08 MPa; the water solution of sodium carbonate is a saturated solution, and the pH value of the alkalized free sodium carbonate is 8-9; the solvent used is a conventional solvent dichloromethane, and the amount of the solvent used is 15-20 times (mass ratio) of the reactant 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde.
4. The post-treatment purification method of the fluoro pranoprazan intermediate according to claim 1 or 2, characterized in that after the extraction in the step (2) is finished, the organic phase is subjected to vacuum concentration, the temperature is controlled below 40 ℃, the vacuum degree is more than or equal to-0.08 MPa, and the solvent is recovered until no distillate exists, so that the crude fluoro pranoprazan intermediate is obtained.
5. The post-treatment purification method of the fluoro pranoprazan intermediate according to claim 1, which is characterized in that: the recrystallization solvent in the step (3) is a mixed solvent and consists of methanol and isopropyl ether; the mass ratio of the crude product of the fluoro pranoprazan intermediate to the mixed solvent to the activated carbon is 1: 4-6: 0.05 to 0.1; methanol: isopropyl ether ═ 1: 2 to 3.
6. the post-treatment purification method of the fluoro pranoprazan intermediate according to claim 1, which is characterized in that: and (3) after air is replaced by nitrogen, decoloring the crude product at the nitrogen pressure of more than or equal to 0.01Mpa at the temperature of 60-65 ℃, crystallizing and filtering at the temperature of 0-5 ℃, and keeping the temperature for crystallization for 0.5 hour.
7. The post-treatment purification method of the fluoro pranoprazan intermediate according to claim 1, which is characterized in that: the drying process in the step (3) is vacuum drying under the nitrogen and vacuum alternative exchange, the drying time is 3-4 hours, the drying temperature is 40-60 ℃, and the vacuum degree is more than or equal to-0.08 MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910976051.0A CN110563699A (en) | 2019-10-15 | 2019-10-15 | Post-treatment purification method of fluoro pranoprazan intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910976051.0A CN110563699A (en) | 2019-10-15 | 2019-10-15 | Post-treatment purification method of fluoro pranoprazan intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110563699A true CN110563699A (en) | 2019-12-13 |
Family
ID=68784802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910976051.0A Withdrawn CN110563699A (en) | 2019-10-15 | 2019-10-15 | Post-treatment purification method of fluoro pranoprazan intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110563699A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124506A (en) * | 2021-03-25 | 2022-09-30 | 广州白云山天心制药股份有限公司 | Preparation method of medicine for digestive system |
| CN115850238A (en) * | 2022-11-29 | 2023-03-28 | 山东新华制药股份有限公司 | Post-treatment method of fluoro pranoprazan intermediate |
-
2019
- 2019-10-15 CN CN201910976051.0A patent/CN110563699A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124506A (en) * | 2021-03-25 | 2022-09-30 | 广州白云山天心制药股份有限公司 | Preparation method of medicine for digestive system |
| CN115124506B (en) * | 2021-03-25 | 2024-04-09 | 广州白云山天心制药股份有限公司 | Preparation method of digestive system medicine |
| CN115850238A (en) * | 2022-11-29 | 2023-03-28 | 山东新华制药股份有限公司 | Post-treatment method of fluoro pranoprazan intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110252395B (en) | Catalyst for preparing high-purity taurine and application thereof | |
| CN103435507B (en) | Preparation method of L-alpha-methyl-3,4-dihydroxyphenylalanine | |
| CN110563699A (en) | Post-treatment purification method of fluoro pranoprazan intermediate | |
| CN112979561B (en) | Post-treatment method for synthesizing 4, 6-dihydroxypyrimidine | |
| CN113880846B (en) | Preparation method of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine | |
| CN107522614B (en) | Method for separating and purifying glutaric acid in mixed dibasic acid by using low-carbon halogenated alkane | |
| CN112028788A (en) | Preparation method for continuously preparing tert-butyl hydrazine hydrochloride | |
| CN111233835A (en) | Preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde | |
| KR20010005573A (en) | Method for debenzylation of dibenzyl biotin | |
| CN112358514A (en) | Synthesis process of arbutin | |
| CN104326901B (en) | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production | |
| CN114249352B (en) | Method for treating wastewater generated in production of 6-methoxy tetralone | |
| CN110606802A (en) | Method for recovering tartaric acid from calcium tartrate by using interfacial reaction | |
| CN106380464A (en) | Preparation method of vonoprazan key intermediate | |
| CN117447355B (en) | Preparation method of milbelin intermediate | |
| CN114685410B (en) | Preparation method of butylphthalide | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN113861093B (en) | Synthesis method of polysubstituted gamma-butyrolactam | |
| CN112375031B (en) | Preparation method of cilnidipine | |
| CN113562912B (en) | Method for treating spironolactone intermediate production wastewater | |
| CN109400468B (en) | Preparation method of L-dibenzoyl dimethyl tartrate | |
| CN113248452A (en) | Method for producing trihydroxyethyl isocyanurate | |
| CN113234033A (en) | Efficient catalyst for synthesizing trihydroxyethyl isocyanurate | |
| CN115073308A (en) | Synthesis method of 1-aminomethyl-1-cyclopropanol | |
| CN113185471A (en) | Trihydroxyethyl isocyanurate decoloring method and decoloring agent |
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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20191213 |