CN114436824A - Preparation method of loxoprofen sodium degradation impurity - Google Patents
Preparation method of loxoprofen sodium degradation impurity Download PDFInfo
- Publication number
- CN114436824A CN114436824A CN202210213574.1A CN202210213574A CN114436824A CN 114436824 A CN114436824 A CN 114436824A CN 202210213574 A CN202210213574 A CN 202210213574A CN 114436824 A CN114436824 A CN 114436824A
- Authority
- CN
- China
- Prior art keywords
- reaction
- loxoprofen sodium
- acid
- sodium degradation
- preparing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
Abstract
The invention discloses a method for synthesizing loxoprofen sodium degradation impurities, and belongs to the field of pharmaceutical chemicals. The method takes 2- (4- ((2-cyclopentyloxy) methyl) phenyl) propionic acid (compound I) as an initial material, and obtains the 2- (4- ((1-hydroxy-2-cyclopentyloxy) methyl) phenyl) propionic acid (compound IV) through enolization, epoxidation, epoxy ring-opening reaction and column chromatography purification. The method has the advantages of simple and efficient synthetic route, high reaction yield, and cheap and easily-obtained materials, solvents and reagents. Can be used for quality control of loxoprofen sodium raw material medicine or used as an impurity reference substance.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of loxoprofen sodium oxidative degradation impurities.
Background
Loxoprofen sodium is a non-steroidal anti-inflammatory drug and is used for anti-inflammatory analgesia of rheumatoid arthritis, lumbago, scapulohumeral periarthritis, neck, shoulder and wrist syndromes and the like, analgesia and anti-inflammation after operations, trauma and tooth extraction, antipyretic analgesia and the like of acute upper respiratory inflammation and the like.
Degradation impurities of loxoprofen sodium are reported in the literature (Journal of Chromatography a,2008,1208,164), as shown in formula IV.
To date, no report has been made on the preparation of this impurity. Therefore, the synthesis of the impurity has great significance for the research on the quality and the impurities of the loxoprofen sodium, can be used for qualitative and quantitative analysis of the impurities in the production of the loxoprofen sodium, and provides guarantee for the medication safety of the loxoprofen sodium.
Disclosure of Invention
The invention aims to provide a method for synthesizing loxoprofen sodium degradation impurities, which can be used for synthesizing the loxoprofen sodium impurity 2- (4- ((1-hydroxy-2-cyclopentanone) methyl) phenyl) propionic acid in a large amount, and the obtained loxoprofen sodium impurity has high purity.
The technical scheme of the invention is as follows:
a synthetic method of loxoprofen sodium degradation impurities comprises the following steps:
(1) carrying out enolization reaction on the compound I and acetic anhydride to obtain an intermediate II;
the structure of the compound I is shown as the formula (I):
the structure of the intermediate II is shown as the formula (II):
(2) carrying out epoxidation reaction on the intermediate II obtained in the step (1) under the condition of a peroxidation reagent to obtain an intermediate III;
the structure of the intermediate III is shown as the formula (III):
(3) and (3) carrying out an epoxy ring-opening reaction on the intermediate III obtained in the step (2) to obtain the loxoprofen sodium degradation impurity IV.
In the step (1), the reaction formula is as follows:
in the step (1), enolization reaction is carried out under the condition of acid catalysis;
the acid is at least one of protonic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, perchloric acid, etc.
The solvent is at least one of ethyl acetate, tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform and carbon tetrachloride.
Preferably, in step (1), the acid used is perchloric acid and the solvent used is dichloromethane.
In the step (1), the reaction temperature is 0-80 ℃, and preferably 10-30 ℃.
In the step (1), after the raw materials are completely reacted, adding alkali to adjust the pH value to 5-6, layering, and concentrating the organic phase under reduced pressure until no fraction is produced, so that the obtained concentrate is directly subjected to the reaction in the step (2) without purification.
In the step (2), the reaction formula is as follows:
in the step (2), the reaction yield is greatly influenced by the type of the peroxidation reagent, wherein the peroxidation reagent is at least one of hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid and t-butyl peroxy alcohol.
In the step (2), the solvent for the epoxidation reaction is at least one selected from dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene and dioxane.
Preferably, in step (2), the peroxidation reagent is peroxyacetic acid, and the solvent for the epoxidation reaction is selected from toluene.
In the step (2), after the reaction is completed, layering is carried out, the organic phase is decompressed and concentrated until no fraction is produced, and the obtained concentrate is directly subjected to the reaction in the step (3) without purification.
In the step (2), the reaction temperature is 0-80 ℃, preferably 10-30 ℃.
In the step (3), the reaction formula is as follows:
in the step (3), the reagent used in the epoxy ring-opening reaction is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
In the step (3), the solvent for the epoxy ring-opening reaction is at least one selected from methanol, ethanol, isopropanol, dioxane and tetrahydrofuran.
Preferably, in step (3), the reagent used in the epoxy ring-opening reaction is potassium carbonate, and the solvent used in the epoxy ring-opening reaction is methanol.
In the step (3), the reaction temperature is 0-80 ℃, preferably 0-20 ℃.
And (3) after the reaction is completed, adding acid to neutralize the solution until the pH value is 5-6, concentrating the filtrate under reduced pressure until no fraction is obtained, and purifying by column chromatography to obtain the loxoprofen sodium degradation impurity IV.
The reaction end point is detected by TLC method in each step of the invention.
The amount of the starting materials used in the present invention is not particularly limited, and the reaction may be carried out in a stoichiometric ratio or in an excess amount.
The dosage of the reaction solvent and the catalyst in the invention is not strictly limited, and can be adjusted according to the dosage of the reaction raw materials: the reaction raw materials are more, the dosage of the reaction solvent and the catalyst is increased, and the dosage of the reaction solvent and the dosage of the catalyst are less.
The invention has the following beneficial effects:
(1) the method for preparing the loxoprofen sodium degradation impurity 2- (4- ((1-hydroxy-2-cyclopentanone) methyl) phenyl) propionic acid in large quantity is provided, can be used for qualitative and quantitative analysis of the loxoprofen sodium degradation impurity, and provides guarantee for the medication safety of the loxoprofen sodium.
(2) The method has the advantages of high conversion rate of each step, less side reaction, no need of column chromatography in the middle step, simpler operation and suitability for mass preparation.
Detailed Description
For better understanding of the technical solutions of the present invention, the following embodiments are further described, but those skilled in the art should recognize that the present invention is not limited to these embodiments.
Example 1
13g of 2- (4- ((2-cyclopentyloxymethyl) phenyl) propionic acid (compound I), 16.35g of acetic anhydride and 150mL of tetrahydrofuran were put into a 250mL three-necked flask, and 2mL of concentrated sulfuric acid was added thereto with stirring, followed by reaction at 10 to 20 ℃ for 4 hours and sampling TLC (ethyl acetate: n-hexane ═ 2:1) to monitor the reaction. After the raw materials react completely, adding sodium bicarbonate solution to adjust the pH value to 5-6, layering, concentrating the organic phase under reduced pressure until no fraction is produced to obtain 14.3g of concentrate, and directly carrying out the next reaction without purification.
And (3) putting 14g of the concentrate obtained in the previous step and 200ml of dichloromethane into a 500ml three-neck bottle, controlling the temperature to be 20-30 ℃, dropwise adding 44g of 50% hydrogen peroxide, and reacting for 20 hours at 20-30 ℃ after dropwise adding. Sample TLC (ethyl acetate: n-hexane ═ 2:1) monitored the reaction. After the raw materials react completely, layering, concentrating the organic phase under reduced pressure until no fraction is produced to obtain 12g of concentrate, and directly carrying out the next reaction without purification.
And (3) adding 12g of the crude product concentrate obtained in the previous step and 200mL of ethanol into a 250mL reaction bottle, controlling the temperature to be 0-10 ℃, adding 10g of sodium hydroxide, reacting for 3 hours at the temperature of 0-10 ℃, and sampling TLC (ethyl acetate: n-hexane ═ 1: 8) to monitor the reaction. After the raw materials completely react, hydrochloric acid is neutralized to pH value of 5-6, filtrate is decompressed and concentrated to no fraction, and 7.8g of 2- (4- ((1-hydroxy-2-cyclopentanone) methyl) phenyl) propionic acid (compound IV) is obtained by column chromatography purification, the HPLC purity is 97.6%, and the total yield of the three-step reaction is 56.5%.
The characterization data for 2- (4- ((1-hydroxy-2-cyclopentyloxy) methyl) phenyl) propanoic acid (compound IV) are as follows:1H NMR(CDCl3)δ：1.49(d,3H),1.72-1.85(m,2H),1.93-2.08(m,2H),2.32-2.35(m,2H),2.76-2.82(m,2H),3.69-3.73(m,1H),71.4(d,2H),7.24(d,2H).13C NMR(CDCl3)δ：17.08,18.10,34.32,34.99,41.21,44.94,79.27,127.60,130.58,134.50,138.49,177.03,180.05.
example 2
13g of 2- (4- ((2-cyclopentyloxymethyl) phenyl) propionic acid (compound I), 16.35g of acetic anhydride and 150mL of dioxane were put into a 250mL three-necked flask, 3mL of hydrochloric acid was added thereto with stirring, the mixture was reacted at 30 to 40 ℃ for 6 hours, and a sample TLC (ethyl acetate: n-hexane: 2:1) was used to monitor the reaction. After the raw materials react completely, adding sodium bicarbonate solution to adjust the pH value to 5-6, layering, concentrating the organic phase under reduced pressure until no fraction is produced to obtain 15.4g of concentrate, and directly carrying out the next reaction without purification.
Adding 15g of the concentrate obtained in the previous step and 200ml of dichloromethane into a 500ml three-necked bottle, controlling the temperature to be 20-30 ℃, adding 10g of m-chloroperoxybenzoic acid, and reacting for 10 hours at 20-30 ℃ after the addition is finished. Sample TLC (ethyl acetate: n-hexane: 2:1) monitored the reaction. After the raw materials completely react, filtering, washing an organic phase by using a sodium bicarbonate solution, layering, and concentrating under reduced pressure until no fraction is produced to obtain 16.3g of a concentrate, and directly carrying out the next reaction without purification in the reaction.
Adding 16g of the crude product concentrate obtained in the previous step and 150mL of ethanol into a 250mL reaction bottle, controlling the temperature to be 0-10 ℃, adding 45g of sodium carbonate, reacting for 12 hours at the temperature of 0-10 ℃, and sampling TLC (ethyl acetate: n-hexane ═ 1: 8) to monitor the reaction. After the raw materials completely react, filtering, concentrating the filtrate under reduced pressure until no fraction is obtained, and purifying by column chromatography to obtain 8.9g of 2- (4- ((1-hydroxy-2-cyclopentanone) methyl) phenyl) propionic acid (compound IV), wherein the HPLC purity is 98.4%, and the total yield of the three-step reaction is 64.3%.
Example 3
13g of 2- (4- ((2-cyclopentyloxymethyl) phenyl) propionic acid (compound I), 16.35g of acetic anhydride, and 50mL of methylene chloride were put into a 250mL reaction flask, 3mL of perchloric acid was added thereto with stirring, and the mixture was reacted at 10 to 20 ℃ for 2 hours with sample TLC (ethyl acetate: n-hexane ═ 2:1) to monitor the reaction. After the raw materials react completely, adding sodium bicarbonate solution to adjust the pH value to 5-6, layering, concentrating the organic phase under reduced pressure until no fraction is produced to obtain 16.3g of concentrate, and directly carrying out the next reaction without purification.
16g of the concentrate obtained in the previous step and 200mL of toluene are put into a 500mL reaction bottle, 44g of peroxyacetic acid is dripped at the temperature of 20-30 ℃, and the reaction lasts for 10 hours after dripping is finished at 20-30 ℃. Sample TLC (ethyl acetate: n-hexane ═ 2:1) monitored the reaction. After the raw materials react completely, adding sodium bicarbonate solution to adjust the pH value to 5-6, layering, concentrating the organic phase under reduced pressure until no fraction is produced to obtain 17.1g of concentrate, and directly carrying out the next reaction without purification.
And (3) putting 17g of the crude product concentrate obtained in the previous step and 400mL of methanol into a 500mL reaction bottle, controlling the temperature to be 0-10 ℃, adding 40g of potassium carbonate, reacting for 12 hours at the temperature of 0-10 ℃, and sampling TLC (ethyl acetate: n-hexane ═ 1: 8) to monitor the reaction. After the raw materials completely react, filtering, adjusting the pH value of the filtrate to 5-6 by hydrochloric acid, concentrating under reduced pressure until no fraction is obtained, and purifying by column chromatography to obtain 10.2g of 2- (4- ((1-hydroxy-2-cyclopentanone) methyl) phenyl) propionic acid (compound IV), wherein the HPLC purity is 97.3 percent, and the total yield of the three-step reaction is 73.7 percent.
Claims (10)
1. The preparation method of the loxoprofen sodium degradation impurity is characterized by comprising the following steps:
(1) carrying out enolization reaction on the compound I and acetic anhydride to obtain an intermediate II;
the structure of the compound I is shown as the formula (I):
the structure of the intermediate II is shown as the formula (II):
(2) carrying out epoxidation reaction on the intermediate II obtained in the step (1) in the presence of a peroxidation reagent to obtain an intermediate III;
the structure of the intermediate III is shown as the formula (III):
(3) carrying out an epoxy ring-opening reaction on the intermediate III obtained in the step (2) to obtain a loxoprofen sodium degradation impurity IV;
the structure of the loxoprofen sodium degradation impurity IV is shown as a formula (IV):
2. the method for preparing loxoprofen sodium degradation impurities as claimed in claim 1, wherein in the step (1), the enolization reaction is performed under acid catalysis;
the acid is at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid and perchloric acid.
3. The method for preparing loxoprofen sodium degradation impurities according to claim 1, wherein in the step (1), after the raw materials completely react, alkali is added to adjust the pH value to 5-6, the layers are separated, the organic phase is concentrated under reduced pressure until no fraction is produced, and the obtained concentrate is directly subjected to the reaction in the step (2) without purification.
4. The method for preparing loxoprofen sodium degradation impurities according to claim 1, wherein the solvent used in step (1) is at least one of ethyl acetate, tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform and carbon tetrachloride.
5. The method for preparing loxoprofen sodium degradation impurity according to claim 1, wherein in the step (2), the peroxidation reagent is at least one of hydrogen peroxide, peracetic acid, m-chloroperoxybenzoic acid and t-butyl peroxy alcohol.
6. The method for preparing loxoprofen sodium degradation impurity according to claim 1, wherein in the step (2), the solvent for epoxidation reaction is at least one selected from dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene and dioxane.
7. The method for preparing loxoprofen sodium degradation impurities as claimed in claim 1, wherein in the step (2), after the reaction is completed, the layers are separated, the organic phase is concentrated under reduced pressure until no fraction is produced, and the obtained concentrate is directly subjected to the reaction in the step (3) without purification.
8. The method for preparing loxoprofen sodium degradation impurities as claimed in claim 1, wherein in the step (3), the reagent used in the epoxy ring-opening reaction is selected from one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
9. The method for preparing loxoprofen sodium degradation impurities as claimed in claim 1, wherein in the step (3), the solvent for the epoxy ring-opening reaction is at least one selected from methanol, ethanol, isopropanol, dioxane and tetrahydrofuran.
10. The method for preparing loxoprofen sodium degradation impurity according to claim 1, wherein in the step (3), after the reaction is completed, acid is added to neutralize the reaction solution to a pH value of 5 to 6, the filtrate is concentrated under reduced pressure until no fraction is obtained, and the loxoprofen sodium degradation impurity IV is obtained by column chromatography purification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210213574.1A CN114436824A (en) | 2022-03-04 | 2022-03-04 | Preparation method of loxoprofen sodium degradation impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210213574.1A CN114436824A (en) | 2022-03-04 | 2022-03-04 | Preparation method of loxoprofen sodium degradation impurity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114436824A true CN114436824A (en) | 2022-05-06 |
Family
ID=81359763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210213574.1A Pending CN114436824A (en) | 2022-03-04 | 2022-03-04 | Preparation method of loxoprofen sodium degradation impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114436824A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115531305B (en) * | 2022-10-21 | 2023-11-07 | 福建汇天生物药业有限公司 | Loxoprofen sodium oral solution and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2664272A1 (en) * | 1990-07-06 | 1992-01-10 | Norsolor Sa | PROCESS FOR THE SELECTIVE EPOXIDATION OF UNSATURATED (METH) ACRYLATES, FUNCTIONAL (METH) ACRYLATES OBTAINED AND THEIR APPLICATION TO THE SYNTHESIS OF NEW POLYMERS. |
| JP2001031623A (en) * | 1999-07-22 | 2001-02-06 | Nippon Petrochem Co Ltd | Production of 2-substituted propionic acid |
| JP2003113177A (en) * | 1995-09-26 | 2003-04-18 | Japan Tobacco Inc | Method for manufacturing amide derivative and intermediate |
| JP2013216636A (en) * | 2012-04-11 | 2013-10-24 | Nipro Patch Co Ltd | Water-containing patch |
| CN104710309A (en) * | 2015-02-05 | 2015-06-17 | 浙江普洛医药科技有限公司 | Synthetic methods of loxoprofen sodium and intermediate thereof |
| CN110204500A (en) * | 2019-07-17 | 2019-09-06 | 九江德思光电材料有限公司 | A kind of preparation method of metconazole |
-
2022
- 2022-03-04 CN CN202210213574.1A patent/CN114436824A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2664272A1 (en) * | 1990-07-06 | 1992-01-10 | Norsolor Sa | PROCESS FOR THE SELECTIVE EPOXIDATION OF UNSATURATED (METH) ACRYLATES, FUNCTIONAL (METH) ACRYLATES OBTAINED AND THEIR APPLICATION TO THE SYNTHESIS OF NEW POLYMERS. |
| JP2003113177A (en) * | 1995-09-26 | 2003-04-18 | Japan Tobacco Inc | Method for manufacturing amide derivative and intermediate |
| JP2001031623A (en) * | 1999-07-22 | 2001-02-06 | Nippon Petrochem Co Ltd | Production of 2-substituted propionic acid |
| JP2013216636A (en) * | 2012-04-11 | 2013-10-24 | Nipro Patch Co Ltd | Water-containing patch |
| CN104710309A (en) * | 2015-02-05 | 2015-06-17 | 浙江普洛医药科技有限公司 | Synthetic methods of loxoprofen sodium and intermediate thereof |
| CN110204500A (en) * | 2019-07-17 | 2019-09-06 | 九江德思光电材料有限公司 | A kind of preparation method of metconazole |
Non-Patent Citations (4)
| Title |
|---|
| KHUSHRAV CRAWFORD ET AL.: "A New Synthesis of Methyl 3-Oxo-2-pentyl-1-cyclopentene-1-acetate", 《SYNLETT》, vol. 7, pages 1127 - 1128 * |
| MOHAMMED K ET.: "Enantioselective Total Synthesis of (+)-Sieboldine A", 《ORGANIC LETTERS》, vol. 19, pages 320 - 323 * |
| TOMONORI MURAKAMI ET AL.: "Identification of degradation products in loxoprofen sodium adhesive tapes by liquid chromatography–mass spectrometry and dynamic pressurized liquid extraction–solid-phase extraction coupled to liquid chromatography–nuclear magnetic resonance spectroscopy", 《JOURNAL OF CHROMATOGRAPHY A》, vol. 1208, pages 164 - 174, XP025504546, DOI: 10.1016/j.chroma.2008.08.076 * |
| 刘安昌, 陈洪, 户业丽: "非甾体抗炎药洛索洛芬钠的合成工艺研究", 中国新药杂志, no. 11, pages 765 - 767 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115531305B (en) * | 2022-10-21 | 2023-11-07 | 福建汇天生物药业有限公司 | Loxoprofen sodium oral solution and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111704573B (en) | Preparation method of rabeprazole chloride and intermediate thereof | |
| CN114436824A (en) | Preparation method of loxoprofen sodium degradation impurity | |
| CN113024384A (en) | Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material | |
| CN111320548A (en) | Synthesis method of anticancer drug intermediate 2-fluoro-3-methyl aminobenzoate | |
| CN108752254B (en) | Preparation method of 2- [1- (ethylsulfonyl) -3-azetidine ] acetonitrile | |
| CN114989061A (en) | Preparation method of brivaracetam | |
| CN111269149B (en) | Production process of 5- (3,3-dimethylguanidino) -2-oxopentanoic acid | |
| CN111646958B (en) | Preparation method of carfilzomib | |
| CN112624957A (en) | Synthetic method of 3-alkyl isoindolinone derivatives | |
| CN116143695B (en) | Synthesis method of 1, 1-difluoro-5-azaspiro [2.5] octane hydrochloride | |
| CN113004300A (en) | Stable isotope labeled patulin and synthetic method thereof | |
| CN114890975B (en) | Compound with fused ring chroman structure and preparation method thereof | |
| CN112125843B (en) | Preparation method of 3-hydroxymethyl-4-phenyl-3, 4-dihydroquinolinone compound | |
| CN114044762B (en) | Preparation method of chlormezanone intermediate | |
| CN117362269A (en) | Alpha-lipoic acid intermediate compound and preparation method thereof | |
| CN114957202B (en) | Preparation method of DL-homocysteine thiolactone hydrochloride | |
| CN117510328B (en) | Preparation method of methyl 4-chlorobutyrate | |
| CN112824387B (en) | 2-methyl nicotinate and preparation method and application thereof | |
| CN111662287B (en) | Preparation of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester | |
| CN112142595B (en) | Preparation method and purification method of ethyl 2,4, 5-trifluoro-benzoylacetate | |
| CN116283748A (en) | Synthesis method of 2, 5-dichloro-3-methoxypyridine | |
| CN117486787A (en) | Preparation method of apixaban intermediate | |
| CN114805286A (en) | Preparation method of naphtho-oxo-thiazepine derivative | |
| CN113861093A (en) | Synthesis method of polysubstituted gamma-butyrolactam | |
| CN116874359A (en) | Synthesis method of naphthalenone compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |