CN111995614B - Preparation method of thiohydroxy acetic anhydride - Google Patents
Preparation method of thiohydroxy acetic anhydride Download PDFInfo
- Publication number
- CN111995614B CN111995614B CN202010981521.5A CN202010981521A CN111995614B CN 111995614 B CN111995614 B CN 111995614B CN 202010981521 A CN202010981521 A CN 202010981521A CN 111995614 B CN111995614 B CN 111995614B
- Authority
- CN
- China
- Prior art keywords
- reaction device
- gas
- solid reaction
- anhydride
- acetic anhydride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/06—Six-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of thiohydroxy acetic anhydride, which comprises the following steps: vaporization of trifluoroacetic anhydride: vaporizing trifluoroacetic anhydride in a vaporizing device for standby; and (3) synthesis of thiohydroxy acetic anhydride: preheating the internal temperature of the suspension state gas-solid reaction device to 45-65 ℃, introducing vaporized trifluoroacetic anhydride into the suspension state gas-solid reaction device, intermittently adding sulfurous diacetic acid from the top of the suspension state gas-solid reaction device, reacting for 2 hours, stopping introducing the vaporized trifluoroacetic anhydride from an air inlet, stopping heating, and leading out the obtained solid product from a discharge port; purification of the thiohydroxy acetic anhydride: washing the solid product with refrigerated anhydrous petroleum ether and anhydrous ether respectively to obtain pure thiohydroxy acetic anhydride. The synthesized thiohydroxy acetic anhydride has high purity and high yield, and the erdosteine prepared by the reaction of the thiohydroxy acetic anhydride serving as a raw material and homocysteine thiolactone hydrochloride has high yield.
Description
Technical Field
The invention relates to preparation of an erdosteine intermediate, and particularly relates to a preparation method of thiohydroxy acetic anhydride.
Background
Erdosteine, chemical name: (+ -) -S- [2- [ N-3- (2-oxo-tetrahydrothienyl) acetamido ] ] mercaptoacetic acid is a phlegm dissolving drug, and is used for treating phlegm viscosity, expectoration difficulty and the like caused by diseases such as acute obstructive bronchitis, chronic obstructive bronchitis, bronchial asthma and the like.
At present, a plurality of methods are used for synthesizing thiohydroxy acetic anhydride which is a key intermediate for synthesizing erdosteine, and the method for synthesizing thiodiglycolic acid and anhydride or acyl chloride is the most common method, such as: the chem.pharm.Bull.50(4)558-562(2002) article discloses a reaction of thiodiglycolic acid with acetic anhydride under reflux for 3 hours under nitrogen, after the reaction is finished, vacuum concentration is carried out, and the concentrate is recrystallized from ethyl acetate to obtain thiohydroxy acetic anhydride (yield 87%). The Chinese pharmaceutical industry impurity 2001,32(12) article discloses that trifluoroacetic anhydride is recovered by mixing thiodiglycolic acid and acetyl chloride under reflux for 3 hours and normal pressure, the remainder is cooled to-5 ℃, placed for 4 hours, filtered, and washed with anhydrous ether (50mL) to obtain white needle-like crystals (yield 80%). Followed by reaction with homocysteine thiolactone hydrochloride to give erdosteine (52.8% yield)
In conclusion, although the synthesis process for synthesizing the key intermediate of erdosteine, namely the thioglycollic anhydride, is simple, the problems of low reaction yield and long reaction time exist, and finally, the problem of how to obtain high-quality and high-yield thioglycollic anhydride exists, so that the problem of low quality and low yield of the subsequent erdosteine synthesis is caused.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and/or disadvantages and to provide at least the advantages described hereinafter.
The invention also aims to provide a preparation method of the thiohydroxy acetic anhydride, which adopts a suspension-state gas-solid reaction device to carry out gas-solid reaction to prepare the thiohydroxy acetic anhydride, eliminates the use of a conventional reaction organic solvent, and synthesizes the high-quality and high-yield thiohydroxy acetic anhydride.
To achieve these objects and other advantages in accordance with the present invention, there is provided a method for preparing thiohydroxyacetic anhydride, comprising the steps of:
1) vaporization of trifluoroacetic anhydride: vaporizing trifluoroacetic anhydride in a vaporizing device for standby;
2) and (3) synthesis of thiohydroxy acetic anhydride: preheating the internal temperature of a suspended gas-solid reaction device to 45-65 ℃, introducing vaporized trifluoroacetic anhydride into the suspended gas-solid reaction device from a gas inlet formed in the bottom of the suspended gas-solid reaction device, intermittently adding sulfurous diacetic acid from a feed inlet formed in the top of the suspended gas-solid reaction device, reacting for 2 hours, stopping introducing the vaporized trifluoroacetic anhydride from the gas inlet, stopping heating, and leading out an obtained solid product from a discharge outlet formed in the bottom of the suspended gas-solid reaction device;
3) purification of the thiohydroxy acetic anhydride: and washing the solid product with anhydrous petroleum ether and anhydrous ether respectively, and freeze-drying to obtain pure thioglycollic anhydride.
Preferably, the method further comprises, before the step 2), the steps of: and detecting the gas in the suspension gas-solid reaction device, so that the suspension gas-solid reaction device is filled with vaporized trifluoroacetic anhydride and does not contain air.
Preferably, in the step 1), the temperature inside the suspended gas-solid reaction device is kept at 45-55 ℃ for 1 hour, and the temperature is kept at 55-65 ℃ for 1 hour.
Preferably, in the step 2), the adding amount of the thiodiglycolic acid is 500g, and the batch adding time is 45 min.
Preferably, in the step 3), the washing step specifically includes: the solid product was washed once with 200mL of refrigerated anhydrous petroleum ether and once with 200mL of refrigerated anhydrous ether.
Preferably, in the step 1), the vaporized trifluoroacetic anhydride is introduced in such an amount that the added sulfurous diacetic acid is stably suspended in the hot gaseous stream of vaporized trifluoroacetic anhydride, and the two are sufficiently contacted to carry out the reaction.
Preferably, a plurality of thermocouples are arranged on the inner side wall of the suspended gas-solid reaction device to detect and control the temperature of the suspended gas-solid reaction device.
Preferably, a plurality of circular pipelines are arranged in parallel in the gasification device, and a plurality of electrically heated catalysts are arranged in the circular pipelines.
Preferably, an air flow disperser is arranged at the bottom of the suspended gas-solid reaction device, and a plurality of air flow through holes are arranged on the surface of the air flow disperser.
The invention at least comprises the following beneficial effects:
1. the preparation method of the thiohydroxy acetic anhydride in the suspension-state gas-solid reaction device reduces the use of organic solvent, not only improves the quality of the thiohydroxy acetic anhydride, but also increases the contact area of the thiodiglycolic acid and trifluoroacetic acid due to the suspension of the thiodiglycolic acid in trifluoroacetic acid airflow, improves the reaction efficiency, shortens the reaction time and improves the yield;
2. the invention arranges a plurality of thermocouples on the inner side wall of the suspension gas-solid reaction device to detect and control the temperature in the suspension gas-solid reaction device, thereby ensuring the uniformity of the temperature in the reaction device;
3. the reaction process of the invention carries out gradient temperature reaction, so that the temperature is increased and the reaction efficiency is improved along with the reduction of the amount of the reactant, i.e. the diacetic acid sulfite;
4. the reaction product of the invention is washed by refrigerated anhydrous petroleum ether and anhydrous ether respectively, so that the residual reaction product and reaction impurities are removed, and the purity of the thiohydroxy acetic anhydride is improved.
5. The bottom of the suspended gas-solid reaction device is provided with the airflow disperser, and the surface of the airflow disperser is provided with a plurality of airflow through holes, so that vaporized trifluoroacetic anhydride is directionally distributed in the inner space of the reaction device, the contact area of sulfurous diacetic acid and trifluoroacetic acid is increased, and the reaction efficiency is improved.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of thiohydroxy acetic anhydride prepared in example 1 of the present invention;
FIG. 2 is a diagram showing the identification of the purity of thiohydroxy acetic anhydride produced in example 1 of the present invention;
FIG. 3 is a schematic structural diagram of an apparatus for preparing thiohydroxy acetic anhydride according to the present invention;
FIG. 4 is a schematic structural diagram of an air flow disperser in the suspension gas-solid reaction apparatus of the present invention.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.
As shown in FIGS. 3 and 4, the apparatus used in the preparation of thioglycollic anhydride according to the present invention comprises: a vaporizing device 1, a suspended gas-solid reaction device 2 and a gas flow detector 3; wherein, vaporizing unit 1 includes: a plurality of circular pipelines 100, a plurality of electrically heated catalysts 110, a liquid inlet 120 and a gas outlet 130 which are arranged in parallel; the suspension gas-solid reaction device 2 comprises: an air inlet 200, an air flow disperser 210, an inlet port 220, a thermocouple 230, an outlet port 240 and a gas recovery port 250.
The working principle of the device is as follows: liquid trifluoroacetic anhydride enters a plurality of circular pipelines 100 through a liquid inlet 120, is heated by a plurality of electric heating catalysts 110 (is connected with a power supply through a plurality of electric wires for heating), is vaporized, enters an air inlet 200 arranged at the bottom of a suspended state gas-solid reaction device 2 from an air outlet 130 through a gas flow detector 3 arranged in the pipeline and close to the suspended state gas-solid reaction device (the vaporized trifluoroacetic anhydride needs to be started and heated to a required temperature before entering the suspended state gas-solid reaction device), is uniformly and directionally dispersed into the space of the suspended state gas-solid reaction device through a plurality of air flow through holes 2100 arranged in an air flow disperser 210, is intermittently added with solid powder thiodiglycolacetic acid from a feed inlet 220 arranged at the top of the suspended state gas-solid reaction device, and is suspended in hot air flow for reaction, wherein, the introduction amount of the vaporized trifluoroacetic acid is based on that the solid powder sulfurous diacetic acid can be stably suspended in hot air flow, the flow is detected by a gas flow detector, the flow that the powder sulfurous diacetic acid is stably suspended in the hot air flow is recorded, and then whether the vaporizing device vaporizes the liquid trifluoroacetic acid is controlled by a controller (not shown in the figure) or not is controlled by the introduction of the liquid trifluoroacetic acid. The controller is in signal connection with the gas flow detector to receive signals of the gas flow detector so as to control whether the liquid trifluoroacetic acid is introduced or not.
The following examples of the present invention all reacted through the above reaction apparatus.
The synthetic route is as follows:
< example 1>
A preparation method of thiohydroxy acetic anhydride comprises the following steps:
1) vaporization of trifluoroacetic anhydride: vaporizing trifluoroacetic anhydride in a vaporizing device for standby;
2) and (3) synthesis of thiohydroxy acetic anhydride: preheating the internal temperature of a suspended gas-solid reaction device to 55 ℃, introducing vaporized trifluoroacetic anhydride into the suspended gas-solid reaction device from an air inlet arranged at the bottom of the suspended gas-solid reaction device, detecting the gas in the suspended gas-solid reaction device by a gas detector, continuously introducing the vaporized trifluoroacetic anhydride to the flow rate which can enable powder thiodiglycolic acid to be stably suspended in high-temperature trifluoroacetic acid airflow when the gas detector shows that the suspended gas-solid reaction device does not have air (the numerical value is set in advance before the reaction starts, and is recorded by the gas flow detector and transmitted to a controller for storage), intermittently adding 500g of thiodiglycolic acid from a feed inlet at the top of the suspended gas-solid reaction device, after 45min of the thiodiglycolic acid is completely added, reacting for 1 hour at 55 ℃, heating by a plurality of thermocouples on the inner wall of the suspended gas-solid reaction device to raise the temperature, stopping heating when the temperature in the reaction device reaches 65 ℃, stopping introducing the vaporized trifluoroacetic anhydride from the air inlet after the reaction is carried out for 1 hour at the temperature, stopping heating by the thermocouple, and leading out the obtained solid product from a discharge hole formed in the bottom of the suspended gas-solid reaction device;
3) purification of the thiohydroxy acetic anhydride: the solid product was washed once with 200mL of refrigerated anhydrous petroleum ether and once with 200mL of refrigerated anhydrous ether to give 431.2g of pure thioglycolic anhydride with a yield of 98%.
< example 2>
A preparation method of thiohydroxy acetic anhydride comprises the following steps:
1) vaporization of trifluoroacetic anhydride: vaporizing trifluoroacetic anhydride in a vaporizing device for standby;
2) and (3) synthesis of thiohydroxy acetic anhydride: preheating the internal temperature of a suspended gas-solid reaction device to 45 ℃, introducing vaporized trifluoroacetic anhydride into the suspended gas-solid reaction device from an air inlet arranged at the bottom of the suspended gas-solid reaction device, detecting the gas in the suspended gas-solid reaction device by a gas detector, continuously introducing the vaporized trifluoroacetic anhydride to the flow capable of stably suspending powder thiodiglycolic acid in high-temperature trifluoroacetic acid airflow when the gas detector shows that the suspended gas-solid reaction device does not have air (the numerical value is set in advance before the reaction starts and is recorded by the gas flow detector and transmitted to a controller for storage), intermittently adding 500g of thiodiglycolic acid from a feed inlet at the top of the suspended gas-solid reaction device, after 45min of the thiodiglycolic acid is completely added, reacting for 1 hour at 45 ℃, heating by a plurality of thermocouples on the inner wall of the suspended gas-solid reaction device to raise the temperature, stopping heating when the temperature in the reaction device reaches 55 ℃, stopping introducing the vaporized trifluoroacetic anhydride from the air inlet after the reaction is carried out for 1 hour at the temperature, stopping heating by the thermocouple, and leading out the obtained solid product from a discharge hole formed in the bottom of the suspended gas-solid reaction device;
3) purification of the thiohydroxy acetic anhydride: the solid product was washed once with 200mL of refrigerated anhydrous petroleum ether and once with 200mL of refrigerated anhydrous ether to give 418.0g of pure thioglycolic anhydride with a 95% yield.
< example 3>
A preparation method of thiohydroxy acetic anhydride comprises the following steps:
1) vaporization of trifluoroacetic anhydride: vaporizing trifluoroacetic anhydride in a vaporizing device for standby;
2) and (3) synthesis of thiohydroxy acetic anhydride: preheating the internal temperature of a suspended gas-solid reaction device to 50 ℃, introducing vaporized trifluoroacetic anhydride into the suspended gas-solid reaction device from an air inlet arranged at the bottom of the suspended gas-solid reaction device, detecting the gas in the suspended gas-solid reaction device by a gas detector, continuously introducing the vaporized trifluoroacetic anhydride to the flow rate which can enable powder thiodiglycolic acid to be stably suspended in high-temperature trifluoroacetic acid airflow when the gas detector shows that the suspended gas-solid reaction device does not have air (the numerical value is set in advance before the reaction starts, and is recorded by the gas flow detector and transmitted to a controller for storage), intermittently adding 500g of thiodiglycolic acid from a feed inlet at the top of the suspended gas-solid reaction device, after 45min of the thiodiglycolic acid is completely added, reacting for 1 hour at 50 ℃, heating by a plurality of thermocouples on the inner wall of the suspended gas-solid reaction device to raise the temperature, stopping heating when the temperature in the reaction device reaches 60 ℃, stopping introducing the vaporized trifluoroacetic anhydride from the air inlet after the reaction is carried out for 1 hour at the temperature, stopping heating by the thermocouple, and leading out the obtained solid product from a discharge hole formed in the bottom of the suspended gas-solid reaction device;
3) purification of the thiohydroxy acetic anhydride: the solid product was washed once with 200mL of refrigerated anhydrous petroleum ether and once with 200mL of refrigerated anhydrous ether to give 426.8g of pure thioglycolic anhydride with a yield of 97%.
< example 4>
The thiohydroxyacetic anhydride prepared in example 1 was subjected to a property test:
nuclear magnetic resonance testing: 400MHz, CDCl3，δ3.62(s,4H,2CH2) From the spectrum obtained in FIG. 1, it was confirmed that the synthesized substance was thiohydroxy acetic anhydride.
And (3) high performance liquid chromatography test:
a high performance liquid chromatograph adopts an Agilent TC-C18 chromatographic column, takes methanol-water (volume ratio is 60: 40) as a mobile phase, has the flow rate of 1.0mL/min and the column temperature of 25 ℃, and uses an ultraviolet detector to carry out the purity determination of the thiohydroxy acetic anhydride at 220 nm. From the high performance liquid chromatogram of FIG. 2, it can be seen that the purity of the produced thiohydroxy acetic anhydride was 100%.
Example 5
Dissolving 20g of homocysteine thiolactone hydrochloride in water, adding sodium bicarbonate to adjust the pH to 7-9, adjusting the temperature of the reaction solution to be lower than 10 ℃, adding thioglycolic anhydride (1.2 equivalent) prepared in example 1, keeping the pH of the reaction solution to be 6-7, reacting for half an hour, adding hydrochloric acid to adjust the pH to be 2-3, separating out and filtering to obtain crude erdosteine, and obtaining 26.6g of erdosteine (the yield is 82%) according to a conventional refining method.
Comparative example 1
500g of solid powder thiodiglycolic acid is dissolved in ethyl acetate, ethyl acetate solution of trifluoroacetic acid (2-2.5 equivalents) is added at room temperature, the mixture is stirred for 24 hours at room temperature, the reaction solution is concentrated, and the concentrated solution is washed by refrigerated petroleum ether to obtain 391.6g of thiohydroxy acetic anhydride with the purity of 95% (detecting that the thiohydroxy acetic anhydride contains ethyl acetate solvent residue by high performance liquid chromatography), and the yield is 89%. The resulting thiohydroxyacetic anhydride was used to synthesize erdosteine 20.4g (yield 63%) according to the procedure of example 5.
Comparative example 2
The preparation is the same as in example 1, except for the step 3) purification of the thiohydroxyacetic anhydride: washing the solid product twice with 200mL of refrigerated anhydrous ether to obtain pure thiohydroxy acetic anhydride with the purity of 99% and the yield of 98%.
Comparative example 3
The preparation is the same as in example 1, except for the step 3) purification of the thiohydroxyacetic anhydride: and washing the solid product twice by using 200mL of refrigerated anhydrous petroleum ether to obtain the pure thiohydroxy acetic anhydride with the purity of 98 percent and the yield of 98 percent.
From the comparison between example 1 and comparative example 1, it can be seen that, the preparation of thiohydroxy acetic anhydride without using the suspension gas-solid reaction device of the present invention not only has a long reaction time, but also has a low purity of the final compound, a residual reaction solvent, and a low yield, and further the yield of the synthesized erdosteine is much lower than that of the thiohydroxy acetic anhydride prepared by the present invention.
As can be seen from a comparison of example 1 and comparative examples 2 and 3, neither the ether wash alone nor the petroleum ether wash alone was as pure as the first petroleum ether wash and then the second ether wash. Different impurities are washed away through washing with the diethyl ether and the petroleum ether respectively, the petroleum ether is adopted firstly and then the diethyl ether is adopted because the petroleum ether residue can be taken away by the diethyl ether adopted later, and the diethyl ether is easy to volatilize compared with the petroleum ether and is easier to volatilize from the product, so that the purity of the product is improved.
In conclusion, the synthesis device and the synthesis method can be used for obtaining high-quality and high-yield thiohydroxy acetic anhydride, and synthesizing erdosteine after the thiohydroxy acetic anhydride is synthesized improves a high-quality intermediate and greatly improves the synthesis yield of the erdosteine.
While embodiments of the invention have been disclosed above, it is not intended to be limited to the uses set forth in the specification and examples. It can be applied to all kinds of fields suitable for the present invention. Additional modifications will readily occur to those skilled in the art. It is therefore intended that the invention not be limited to the exact details and illustrations described and illustrated herein, but fall within the scope of the appended claims and equivalents thereof.
Claims (3)
1. A preparation method of thiohydroxy acetic anhydride comprises the following steps:
1) vaporization of trifluoroacetic anhydride: vaporizing trifluoroacetic anhydride in a vaporizing device for standby;
2) and (3) synthesis of thiohydroxy acetic anhydride: preheating the internal temperature of a suspended state gas-solid reaction device to 45-65 ℃, introducing vaporized trifluoroacetic anhydride into the suspended state gas-solid reaction device from an air inlet formed in the bottom of the suspended state gas-solid reaction device, detecting gas in the suspended state gas-solid reaction device to ensure that the suspended state gas-solid reaction device is filled with the vaporized trifluoroacetic anhydride and does not contain air, intermittently adding sulfurous diacetic acid from an air inlet formed in the top of the suspended state gas-solid reaction device, reacting for 2 hours, stopping introducing the vaporized trifluoroacetic anhydride from the air inlet, stopping heating, and leading out an obtained solid product from an air outlet formed in the bottom of the suspended state gas-solid reaction device;
the bottom of the suspended gas-solid reaction device is provided with an airflow disperser, the surface of the airflow disperser is provided with a plurality of airflow through holes, vaporized trifluoroacetic anhydride is uniformly and directionally dispersed into the space of the suspended gas-solid reaction device through the airflow through holes, the introduction amount of the vaporized trifluoroacetic anhydride is such that the added sulfurous diacetic acid is stably suspended in the hot airflow of the vaporized trifluoroacetic anhydride, and the vaporized trifluoroacetic anhydride and the sulfurous diacetic acid are fully contacted for reaction; the adding amount of the thiodiglycolic acid is 500g, and the intermittent adding time is 45 min;
3) purification of the thiohydroxy acetic anhydride: washing the solid product with 200mL of refrigerated anhydrous petroleum ether once, then washing the solid product with 200mL of refrigerated anhydrous ether once, and freeze-drying the washed solid product to obtain pure thioglycollic anhydride;
wherein the temperature in the suspension state gas-solid reaction device is kept for 1 hour at 45-55 ℃, and the temperature is kept for 1 hour at 55-65 ℃.
2. The process for preparing thiohydroxy acetic anhydride as claimed in claim 1, wherein a plurality of thermocouples are provided on the inner sidewall of the suspended solid gas-solid reaction device to detect and control the temperature of the suspended solid gas-solid reaction device.
3. A process for preparing thiohydroxy acetic anhydride as claimed in claim 1, wherein a plurality of circular tubes are disposed in parallel in said vaporization apparatus, and a plurality of electrically heated catalysts are disposed in said circular tubes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010981521.5A CN111995614B (en) | 2020-09-17 | 2020-09-17 | Preparation method of thiohydroxy acetic anhydride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010981521.5A CN111995614B (en) | 2020-09-17 | 2020-09-17 | Preparation method of thiohydroxy acetic anhydride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111995614A CN111995614A (en) | 2020-11-27 |
| CN111995614B true CN111995614B (en) | 2022-01-04 |
Family
ID=73475637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010981521.5A Active CN111995614B (en) | 2020-09-17 | 2020-09-17 | Preparation method of thiohydroxy acetic anhydride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111995614B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116283893B (en) * | 2023-03-22 | 2024-04-26 | 阜阳欣奕华制药科技有限公司 | Preparation method of thiohydroxy acetic anhydride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928298A (en) * | 2009-06-18 | 2010-12-29 | 浙江新安化工集团股份有限公司 | Method and device for producing N-phosphono methyl glycine |
| CN101941963A (en) * | 2010-04-22 | 2011-01-12 | 浙江康乐药业股份有限公司 | Synthesis method of erdosteine |
-
2020
- 2020-09-17 CN CN202010981521.5A patent/CN111995614B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928298A (en) * | 2009-06-18 | 2010-12-29 | 浙江新安化工集团股份有限公司 | Method and device for producing N-phosphono methyl glycine |
| CN101941963A (en) * | 2010-04-22 | 2011-01-12 | 浙江康乐药业股份有限公司 | Synthesis method of erdosteine |
Non-Patent Citations (2)
| Title |
|---|
| New Heterocyclic Product Space for the Castagnoli−Cushman Three-Component Reaction;Dmitry Dar’in等;《 Organic Letters》;20150730;第17卷(第15期);supporting information第S2-S3页 * |
| 厄多司坦的合成;李飞等;《中国医药工业杂志》;20011220;第32卷(第12期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111995614A (en) | 2020-11-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105622535B (en) | A kind of preparation method of LCZ696 | |
| CN108191749B (en) | Preparation method of flonicamid and intermediate 4-trifluoromethyl nicotinic acid thereof | |
| CN104447600B (en) | A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application | |
| CN110330500B (en) | Stereoselective synthesis method of 6 beta-hydroxy-7, 8-dihydro-morphine derivative | |
| CN111995614B (en) | Preparation method of thiohydroxy acetic anhydride | |
| CN113620868A (en) | Torasemide new impurity and preparation method thereof | |
| CN106588903A (en) | Rivaroxaban intermediate impurities and preparation and separation and purification methods thereof | |
| CN108840816A (en) | Acid imide midbody compound and its preparation method and application | |
| CN104761599B (en) | A kind of preparation method of the O D glucuronic acids of 5,4 ' dihydroxyflavone 7 | |
| CN114773176B (en) | Chlorpheniramine maleate impurity and preparation method and application thereof | |
| CN105753733A (en) | AHU377 crystal form and preparation method and uses thereof | |
| CN110092786A (en) | The manufacturing method of rutaecarpin | |
| CN110563795B (en) | Preparation method and application of diosgenin derivative containing 1,3,4 oxadiazole or 1,3,4 thiadiazole fragment | |
| CN110330447B (en) | Preparation method and application of nafamostat mesylate intermediate | |
| CN105753732A (en) | Crystal form of AHU377 as well as preparation method and application thereof | |
| CN113024472A (en) | Preparation method of lung cancer targeted drug dacomitinib | |
| CN114181270B (en) | Canagliflozin impurity, preparation method and removal method | |
| CN111875661B (en) | Method for separating and purifying abiraterone and dimer thereof | |
| CN111116597A (en) | Preparation method of nalbuphine free alkali | |
| CN115572262B (en) | Isoquinoline derivative and preparation method thereof | |
| CN113135899B (en) | Benzocycloheptapyridine compounds, process for their preparation and their use | |
| CN114685374B (en) | Novel process for synthesizing Olaparib | |
| CN110105371B (en) | Impurities in doladazole bulk drug and preparation method thereof | |
| CN118324672A (en) | Production process and purification method of high-purity Fudosteine | |
| CN114634439A (en) | Preparation method of etodolac impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |