CN107488196B - Preparation method of phosphate - Google Patents
Preparation method of phosphate Download PDFInfo
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- CN107488196B CN107488196B CN201710437428.6A CN201710437428A CN107488196B CN 107488196 B CN107488196 B CN 107488196B CN 201710437428 A CN201710437428 A CN 201710437428A CN 107488196 B CN107488196 B CN 107488196B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention relates to a preparation method of phosphate, belonging to the technical field of pharmacy. The method provided by the invention can obtain high-quality products with high yield by carrying out reaction and post-treatment on the raw materials, phenol and alkali after water separation treatment under certain conditions and adding thionyl chloride; the method is simple and convenient to operate, smooth in treatment after reaction, easy in solvent recovery and suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of phosphate, belonging to the technical field of pharmacy.
Background
Tenofovir alafenamide (Tenofovir alafenamide) is a novel nucleoside reverse transcriptase inhibitor, has a good antiviral effect and good kidney and bone safety, is approved in Europe and America, is used for treating chronic hepatitis B virus infected adult patients with compensatory liver diseases, and has a structure shown in the following formula:
in the process of preparing tenofovir alafenamide, an intermediate compound (02) shown as the following formula (02) needs to be prepared firstly:
the compound (02) represented by the formula (02) is a phosphoric acid monoester compound, and in the production process thereof, a monoester compound may be hardly produced or a diester compound may be easily produced depending on the reaction conditions, and therefore, it is necessary to investigate the reaction conditions.
Disclosure of Invention
Summary of The Invention
The present invention is directed to a process for producing a compound (02) represented by formula (02), which comprises: mixing a compound (01) shown as a formula (01), phenol, alkali and a nonpolar reaction solvent, performing reflux water separation treatment, then cooling, adding thionyl chloride, and optionally adding an alkalizer; after the addition, heating and controlling the temperature to react; after the reaction is finished, post-treatment is carried out to obtain a compound (02),
definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
The numerical ranges of the present invention, whether or not the term "about" is used before referring to a numerical range of ± 20% of the specified numerical value.
Detailed Description
In the prior art, a common method for preparing the compound (02) from the compound (01) is that the compound (01) and thionyl chloride react for a period of time in a polar solvent, then activated phenol is added for reaction, and a target product is obtained after treatment; in addition, a method of obtaining a target product by promoting the reaction using a condensing agent such as DCC (dicyclohexylcarbodiimide) has been proposed in the prior art.
Because the compound (01) has low activity and high polarity, in the prior art, in order to ensure that the compound (01) can completely react within a certain time, the reaction is usually carried out in a polar solvent under the heating condition so as to ensure that the reaction system is homogeneous, the raw material reaction is more sufficient, and the generation of diester byproducts can be reduced. However, these methods have low yield, complicated reaction operation, high raw material cost, or large pressure for treating three wastes. Meanwhile, a polar solvent is used as a reaction solvent, the reaction solvent is generally required to be evaporated for post-treatment so as to further obtain a product, and if the solvent is not evaporated and water is added for crystallization, the solvent is complicated to recover, so that the method is not beneficial to industrial production. Therefore, it is necessary to find a method for producing the compound (02) with high yield, low cost and easy operation.
The inventor of the present invention found through research that the object of reacting the compound (01) with thionyl chloride to generate a phosphoryl chloride compound and then promoting the generation of a target compound cannot be achieved well; and firstly, the compound (01), the phenol, the alkali and the nonpolar reaction solvent are mixed, and after reflux water separation treatment, water possibly existing in the raw materials can be well removed, and meanwhile, the phenol is activated, so that the reaction balance is favorably moved to the direction of a target product after the thionyl chloride is added, and the target product is favorably obtained. The method of adding the alkali first is simple and convenient to operate, meanwhile, the nonpolar solvent is used, so that the treatment after the reaction is smooth, the solvent is easy to recycle, a high-quality product can be obtained with high yield, and the industrial production is easy to realize.
The present invention provides a method for producing a compound (02) represented by formula (02), which comprises: mixing a compound (01) shown as a formula (01), phenol, alkali and a nonpolar reaction solvent, performing reflux water separation treatment, then cooling, adding thionyl chloride, and optionally adding an alkalizer; after the addition, heating and controlling the temperature to react; after the reaction is finished, carrying out post-treatment to obtain a compound (02), wherein the reaction formula is shown as the following formula:
wherein the base is an alkali metal hydroxide, an alkaline earth metal hydroxide, or a combination thereof. In some embodiments, the base is sodium hydroxide, sodium hydride, potassium hydroxide, or a combination thereof. In some embodiments, the base is sodium hydroxide, facilitating the reaction and post-reaction processing.
The nonpolar solvent is toluene, xylene, n-heptane, cyclohexane, n-hexane, carbon tetrachloride, benzene or a mixed solvent thereof. In some embodiments, the non-polar solvent is toluene. In some embodiments, the non-polar solvent is cyclohexane.
The amount of the nonpolar solvent used is 5mL to 20mL per gram of compound (01). In some embodiments, the non-polar solvent is used in an amount of 8mL to 15mL per gram of compound (01). In some embodiments, the amount of the non-polar solvent used is from 8mL to 12mL per gram of compound (01), which facilitates the reaction.
The time of the reflux water diversion treatment is more than 0.1 hour. In some embodiments, the time for the refluxing water-splitting treatment is 2 hours to 7 hours. In some embodiments, the reflux water-splitting treatment is performed for 3 hours to 6 hours, which facilitates the reaction.
And the temperature is reduced to be lower than the boiling point of thionyl chloride. In some embodiments, the reducing is reducing the temperature to between 0 ℃ and 60 ℃. In some embodiments, the reducing is reducing the temperature to below 50 ℃. In some embodiments, the temperature reduction is to reduce the temperature to 20 ℃ to 50 ℃ to facilitate operation. In some embodiments, the temperature reduction is to reduce the temperature to 25 ℃ to 45 ℃ to facilitate operation.
In the method for producing the compound (02), an alkalifying agent may or may not be added during the reaction. In some embodiments, in the method for preparing compound (02), an alkalization agent is added during the reaction to facilitate the reaction. The alkalizer may be sodium carbonate, potassium carbonate, or a combination thereof. The charging molar ratio of the alkalizer to the compound (01) may be 1:1 to 1: 3.
In the method for preparing the compound (02), the reaction is carried out by heating and controlling the temperature to be 70-120 ℃. In some embodiments, the reaction is facilitated by heating and controlling the temperature to be 75-95 ℃. In some embodiments, the reaction is carried out by heating and controlling the temperature to be 80-90 ℃, which is beneficial to obtaining a product with higher quality.
The feeding molar ratio of the compound (01) to the phenol is 1:1.1-1: 1.5. In some embodiments, a molar feed ratio of compound (01) to phenol of 1:1.3 is beneficial for better product yield.
The feeding molar ratio of the compound (01) to the alkali is 1:1.05-1: 1.5. In some embodiments, compound (01) to base is charged at a molar ratio of 1:1.27, which facilitates better product availability.
The feeding molar ratio of the compound (01) to the thionyl chloride is 1:1.2-1: 2.0. In some embodiments, the molar ratio of compound (01) to thionyl chloride feed is in the range of 1:1 to 1:1.5, which is advantageous for obtaining the product. In some embodiments, compound (01) and thionyl chloride are fed in a molar ratio of 1:1.35, which facilitates better product availability.
The reaction time of the temperature-controlled reaction is 12 hours to 24 hours. In some embodiments, the reaction is carried out for a reaction time of 12 hours to 18 hours, which is more complete and results in higher product quality.
The method for preparing the compound (02) is characterized in that after the reaction is finished, post-treatment is carried out, and the post-treatment comprises the following steps: cooling the reaction system, adding water to quench the reaction, adding an alkali solution to adjust the pH to 6-9, separating liquid, adjusting the pH of a water phase to 1-3 with an acid, stirring for crystallization, separating to obtain a solid, and removing the solvent to obtain the compound (02).
In the context of the present invention, completion of the reaction means monitoring the end of the reaction by High Performance Liquid Chromatography (HPLC), and the reaction is considered complete when the HPLC purity of compound (01) is less than or equal to 1.0%, and the reaction time is usually less than 24 hours.
The step of cooling the reaction system comprises the step of cooling the reaction system to 0-40 ℃. In some embodiments, the reaction system is cooled to a temperature of 10 ℃ to 40 ℃, so that the reaction treatment is facilitated. In some embodiments, the temperature of the reaction system is reduced to 15-35 ℃ to facilitate the reaction treatment.
The reaction was quenched by addition of water, 3mL to 6mL of water per gram of compound (01). In some embodiments, the quenching with water, 3mL to 5mL of water per gram of compound (01), facilitates the reaction process.
After quenching, the pH is adjusted to 6-9 by the addition of an alkaline solution, which may include an aqueous solution containing sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination thereof, to facilitate high yield of the product.
The pH is adjusted to 1.0-3.0 with an acid, and usable acids include hydrochloric acid, acetic acid, trifluoroacetic acid, phosphoric acid, or sulfuric acid, etc. In some embodiments, adjusting the pH to 1.5-3.0 with hydrochloric acid facilitates the obtaining of the product.
The nonpolar solvent in the reaction can be recovered from the organic phase obtained by separating the liquid through simple distillation, and the recovered nonpolar solvent can be used for the reaction again.
The temperature of the crystallization can be 0 ℃ to 60 ℃. In some embodiments, the temperature of the devitrification is from 10 ℃ to 60 ℃. In some embodiments, the temperature of the crystallization is from 20 ℃ to 40 ℃ to facilitate obtaining the product. In some embodiments, the temperature of the crystallization is between 25 ℃ and 35 ℃, which is beneficial for obtaining high-quality products.
The stirring crystallization time can be 0.5-15 hours. In some embodiments, the time for the stirred crystallization is from 1 hour to 12 hours. In some embodiments, the time for the stirred crystallization is from 1 hour to 10 hours. In some embodiments, the time for the stirred crystallization is from 1 hour to 6 hours. In some embodiments, the stirring crystallization time is 4 hours, which is beneficial to obtain the product with high yield.
After separation to obtain a solid, the obtained solid may be subjected to washing, slurrying or other operations with water, methanol, ethanol or a combination thereof to further improve its purity or quality.
The obtained solid can be subjected to vacuum drying or the like to remove the solvent.
In some embodiments, the post-processing comprises: cooling the reaction system to 10-60 ℃, adding water for quenching, adding a sodium hydroxide aqueous solution for adjusting the pH to 6-9, separating liquid, adjusting the pH of a water phase to 1.5-3.0 by hydrochloric acid, then controlling the temperature to be 20-40 ℃, stirring for crystallization for 2-5 hours, separating to obtain a solid, and removing the solvent to obtain the compound (02).
In some embodiments, the post-processing comprises: cooling the reaction system to 20-40 ℃, adding water for quenching, adding a sodium hydroxide solution for adjusting the pH to 6-9, separating liquid, adjusting the pH of a water phase to 1.5-3.0 by using concentrated hydrochloric acid, then controlling the temperature to 20-40 ℃, stirring for crystallization for 2-5 hours, filtering, and drying the obtained solid to obtain the compound (02).
In some embodiments, a method of making compound (02) comprises: mixing the compound (01) shown in the formula (01), phenol, sodium hydroxide and toluene, performing reflux water separation treatment for 2 to 6 hours, then cooling to below 50 ℃, adding thionyl chloride, and optionally adding potassium carbonate; after the addition, heating and controlling the temperature to be 75-95 ℃ for reaction; after the completion of the reaction, post-treatment was carried out to obtain compound (02).
In some embodiments, a method of making compound (02) comprises: mixing the compound (01) shown in the formula (01), phenol, sodium hydroxide and cyclohexane, performing reflux water separation treatment for 2 to 6 hours, then cooling to 25 to 45 ℃, adding thionyl chloride, and adding potassium carbonate; after the addition, the temperature is controlled to be 75-95 ℃ for reaction for 12-18 hours; after the reaction is finished, cooling the reaction system to 20-40 ℃, adding water for quenching, adding a sodium hydroxide solution for adjusting the pH to 6-9, separating liquid, adjusting the pH of a water phase to 1.5-3.0 by hydrochloric acid, stirring at 20-40 ℃ for crystallization for 3-6 hours, separating to obtain a solid, and removing the solvent to obtain the compound (02).
Compared with the prior art, the method for preparing the compound (02) has the advantages of high yield, low cost, simple and convenient reaction and post-treatment operation, and cheap and easily-obtained reaction reagents. Meanwhile, the nonpolar solvent is adopted, so that the solvent is easy to recover and reuse, the cost is reduced, and the three-waste treatment pressure is greatly reduced.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, g represents g, mL represents mL, h represents h, and DMF represents N, N-dimethylformamide.
In the present invention, room temperature means a temperature of 15 ℃ to 35 ℃.
Example 1
At room temperature, 100g of the predried compound (01), 42.6g of phenol, 17.74g of sodium hydroxide and 100mL of toluene are added into a reaction bottle, and heating reflux is carried out to separate water for 4 hours; then the internal temperature of the reaction system is reduced to 40 ℃ to 45 ℃, 48.12g of potassium carbonate and 62.13g of thionyl chloride are added at one time, the internal temperature of the system is increased to 80 ℃ to 90 ℃ after the addition, and the temperature is kept and the stirring is carried out for 14 hours. Cooling the reaction system to room temperature, adding 450g of water to quench the reaction, and slowly adding 30% sodium hydroxide (mass fraction) to adjust the pH value to 6.0-9.0; separating, retaining water phase, adjusting pH of the water phase to 1.5-3.0 with concentrated hydrochloric acid, stirring at room temperature for 8 hr, vacuum filtering, and vacuum drying the filter cake at 90 deg.C for 24 hr to obtain 102.48g of off-white solid compound (02) with yield of about 81.01%.
Example 2
At room temperature, 100g of the pre-dried compound (01), 39.32g of phenol, 16.38g of sodium hydroxide and 100mL of toluene are added into a reaction bottle, reflux and water diversion are carried out for 4 hours, then the internal temperature of the reaction system is reduced to 35-45 ℃, 55.92g of thionyl chloride is added at one time, the internal temperature of the system is raised to 80-90 ℃ after the addition, and the temperature is kept and the stirring is carried out for 16 hours. Cooling the reaction system to 25-35 ℃, adding 300g of drinking water to quench the reaction, slowly adding 30% sodium hydroxide (mass fraction) to adjust the pH to 6.0-9.0, separating, retaining the water phase, adjusting the pH of the water phase to 1.5-3.0 by using concentrated hydrochloric acid, stirring at room temperature for 12 hours, carrying out suction filtration, and carrying out vacuum drying on the filter cake at 90 ℃ for 24 hours to obtain 92.63g of white-like solid compound (02) with the yield of about 73.23%.
Example 3
At room temperature, 100g of the predried compound (01), 42.6g of phenol, 17.74g of sodium hydroxide and 100mL of cyclohexane are added into a reaction bottle, reflux and water diversion are carried out for 4 hours, the temperature in the system is reduced to 35-40 ℃, 48.12g of potassium carbonate and 55.92g of thionyl chloride are added at one time, then, the temperature in the system is increased to 85-95 ℃ after the addition, and the mixture is stirred for 18 hours under heat preservation. Cooling the reaction system to 30-35 ℃, adding 450g of drinking water to quench the reaction, slowly adding 30% sodium hydroxide (mass fraction) to adjust the pH to 6.0-9.0, stirring for 0.5 hour, separating liquid, reserving a water phase, adjusting the pH of the water phase to 1.5-3.0 by using concentrated hydrochloric acid, stirring for 6 hours at room temperature, performing suction filtration, and performing vacuum drying on a filter cake at 90 ℃ for 24 hours to obtain 86.53g of white-like solid compound (02) with the yield of about 68.40%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (8)
1. A process for preparing a compound represented by formula (02), comprising the steps of:
mixing the compound (01), phenol, alkali and a nonpolar reaction solvent, cooling the system after refluxing and water separation, adding thionyl chloride, and optionally adding an alkalizer; after the addition, heating and controlling the temperature to react; wherein the base is an alkali metal hydroxide, an alkaline earth metal hydroxide, or a combination thereof; the alkalizer is sodium carbonate, potassium carbonate or a combination thereof.
2. The method according to claim 1, wherein the nonpolar reaction solvent is toluene, xylene, n-heptane, cyclohexane, n-hexane, carbon tetrachloride, benzene or a mixed solvent thereof.
3. The method of claim 1, wherein the heating temperature-controlled reaction temperature is 70 ℃ to 120 ℃.
4. The process according to claim 1, wherein the molar ratio of compound (01) to phenol fed is from 1:1.1 to 1: 1.5.
5. The process according to claim 1, wherein the molar ratio of compound (01) to base fed is from 1:1.05 to 1: 1.5.
6. The process according to claim 1, wherein the molar ratio of compound (01) to thionyl chloride is fed in the range of 1:1.2 to 1: 2.0.
7. The process according to claim 1, wherein the molar ratio of compound (01) to the basifying agent is from 1:1 to 1: 3.
8. The process according to claim 1, the process for producing the compound represented by formula (02) further comprising a post-treatment step comprising: cooling the reaction system, adding water for quenching, adding an alkali solution to adjust the pH to 6-9, separating liquid, adjusting the pH of a water phase to 1.0-3.0 by using an acid, stirring for crystallization, separating to obtain a solid, and removing the solvent to obtain the compound (02).
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| CN201610421325 | 2016-06-13 | ||
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665043A (en) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | Tenofovir prodrug and medical application thereof |
| WO2014068265A1 (en) * | 2012-10-29 | 2014-05-08 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
| CN104151360A (en) * | 2013-05-14 | 2014-11-19 | 北京美倍他药物研究有限公司 | Phosphoric acid/phosphonic acid derivatives and medical applications thereof |
| WO2015040640A2 (en) * | 2013-09-20 | 2015-03-26 | Laurus Labs Private Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
| CN104955818A (en) * | 2012-12-06 | 2015-09-30 | 默沙东公司 | Nucleoside kinase bypass compositions and methods |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140288025A1 (en) * | 2013-03-13 | 2014-09-25 | Catabasis Pharmaceuticals, Inc. | Fatty acid antiviral conjugates and their uses |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665043A (en) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | Tenofovir prodrug and medical application thereof |
| WO2014068265A1 (en) * | 2012-10-29 | 2014-05-08 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
| CN104955818A (en) * | 2012-12-06 | 2015-09-30 | 默沙东公司 | Nucleoside kinase bypass compositions and methods |
| CN104151360A (en) * | 2013-05-14 | 2014-11-19 | 北京美倍他药物研究有限公司 | Phosphoric acid/phosphonic acid derivatives and medical applications thereof |
| WO2015040640A2 (en) * | 2013-09-20 | 2015-03-26 | Laurus Labs Private Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |