CN113501757B - Preparation and refining method of high-purity diethyl chloropropionate - Google Patents
Preparation and refining method of high-purity diethyl chloropropionate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C67/54—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
Abstract
The invention relates to a preparation and refining method of high-purity diethyl chloropropionate, belonging to the technical field of chemical preparation. The preparation method comprises the steps of taking diethyl malonate as a starting material, carrying out substitution, reacting with sodium sulfite, and then carrying out rectification purification to obtain high-purity diethyl chloropropionate; compared with the prior art, the method has the advantages that the used raw materials are cheap and easy to obtain, and the production cost is reduced; the purity of the product after rectification and purification reaches up to 99 percent; the reaction time is short, and the production period is shortened; complex post-treatment operation is not needed in the reaction, and the operation is simple; the compound I rectified at the end of the reaction can be recycled, and the atom economy of the reaction is good; the reaction does not produce a large amount of waste liquid, and is more environment-friendly.
Description
Technical Field
The invention relates to the technical field of chemical preparation, in particular to a preparation and refining method of high-purity diethyl chloropropionate.
Background
Diethyl chloromalonate, CAS number: 14064-10-9 is an important organic synthesis intermediate and a medical intermediate, and is widely applied to the research and development process of laboratories and the chemical production process. The chemical structural formula is shown as the following formula II:
the prior preparation method of chloro-diethyl malonate mainly adopts diethyl malonate as a raw material to react with a chloro-reagent to prepare chloro-diethyl malonate; the chlorinating agent used includes chlorine gas, N-chlorosuccinimide and the like, 1, 2-dichloroethane, chloroform, magnesium chloride, etc. The above preparation method has many disadvantages: the production of dichloro-substituted impurities is unavoidable in the reaction, and the removal of the dichloro impurities is not easy, so that the product purity is influenced, the waste of raw materials is caused, and the high-purity diethyl chloromalonate is difficult to obtain.
The synthetic route of the intermediate II disclosed in Chinese patent CN103449946 is as follows: taking diethyl malonate as a starting material, and carrying out substitution reaction with a chlorinated reagent and a derivative of N-chlorosuccinimide to prepare an intermediate II. The route uses a plurality of reagents, including ammonium acetate, methanol and water, and the used bromization reagent is expensive, high in cost, troublesome in post-treatment, low in product purity and low in yield.
The route of the intermediate II disclosed by the Chinese patent CN101279948 is as follows: taking diethyl malonate as a starting material, and carrying out substitution reaction on the diethyl malonate and N-chlorosuccinimide to obtain an intermediate II. The reaction steps of the route are complicated, the product is not easy to purify, multiple post-treatments are involved in the route, the generated three wastes are more, the route is not environment-friendly, and the route is not suitable for industrial amplification.
Therefore, research on a preparation method of diethyl chloropropionate is still needed to obtain a preparation method which is simple and convenient to operate, high in yield, high in purity, low in cost, environment-friendly and suitable for industrial large-scale production.
Disclosure of Invention
Aiming at the technical problems of low yield, poor purity, complex reaction steps, high cost, more generated three wastes and environmental pollution of the preparation method of the chloro-diethyl malonate, the invention provides the preparation method of the chloro-diethyl malonate, and the method has the characteristics of simple operation, high yield, good product purity, low cost, good atom economy, less generated three wastes and suitability for industrial amplification. The invention provides a preparation method of high-purity diethyl chloropropionate. Diethyl chloromalonate, named compound II, has the following structure:
according to the preparation method provided by the invention, a compound I can be used as an initial material, a compound II and a compound III are obtained through substitution reaction, and optional post-treatment is carried out; then sodium sulfite is added to prepare a compound II and a compound I, and optional post-treatment is carried out; rectifying and purifying to obtain a high-purity compound II; the specific reaction route is as follows:
in one aspect, the present invention provides a process for the preparation of compound II, comprising the steps of a: the compound I and sulfonyl chloride carry out substitution reaction at the reaction temperature to prepare a compound II and a compound III,
the reaction temperature of the substitution reaction may be 45 ℃ to 85 ℃.
In some embodiments, the reaction temperature of the substitution reaction is from 50 ℃ to 80 ℃; or the reaction temperature of the substitution reaction is 55-75 ℃. In some embodiments, the substitution reaction is at a reaction temperature of 60 ℃ to 70 ℃. In some embodiments, the substitution reaction is carried out at a reaction temperature of 65 ℃ to facilitate the reaction.
The molar ratio of compound I to sulfonyl chloride in step a may be 1.8-1.
In some embodiments, the molar ratio of compound I to sulfonyl chloride in step a is 1. In some embodiments, the molar ratio of compound I to sulfonyl chloride in step a is 1 to 1.1. In some embodiments, the molar ratio of compound I to sulfonyl chloride in step a is 1.05, which facilitates the formation and obtaining of the product.
The reaction time of the substitution reaction can be 10min to 3h.
In some embodiments, the reaction time for the substitution reaction is from 30min to 2.5h; or the reaction time of the substitution reaction is 45min-2h; or the reaction time of the substitution reaction is 1h-1.5h.
The preparation method of the compound II, step A, can be carried out under the protection of nitrogen.
According to the preparation method of the compound II, after the reaction in the step A is completed, the post-treatment is optionally carried out. In some embodiments, the method of preparing compound II, the post-treatment of step a, comprises: and (3) at the temperature of between 50 and 80 ℃, vacuumizing excess sulfur dioxide and hydrogen chloride gas in the reaction system to obtain a mixture of a compound II and a compound III.
In some embodiments, the reaction described in step a completely comprises: the compound I is monitored by GC, and the reaction is complete when 4% -8% of the compound I remains.
In some embodiments, a method of preparing compound I comprises step a: and (3) carrying out substitution reaction on the compound I and sulfonyl chloride at the temperature of 50-80 ℃, and optionally carrying out post-treatment after the reaction is finished to prepare a mixture of a compound II and a compound III.
In some embodiments, a method of preparing compound I comprises step a: and (3) carrying out substitution reaction on the compound I and sulfonyl chloride at the temperature of 50-80 ℃, stopping the reaction after the reaction is finished, and vacuumizing excess sulfur dioxide and hydrochloric acid gas in a reaction system at the temperature of 50-80 ℃ to prepare a mixture of a compound II and a compound III.
In some embodiments, a method of preparing compound II may further comprise step B: reacting the compound II and the compound III obtained in the step A with a sodium sulfite aqueous solution at a reaction temperature to obtain a compound II and a compound I,
the reaction temperature of the step B is 30-60 ℃. In some embodiments, the reaction temperature is from 40 ℃ to 50 ℃.
And the concentration of the sodium sulfite aqueous solution in the step B is 10-30%. In some embodiments, the concentration of the aqueous solution of sodium sulfite in step B is 15% to 25%. In some embodiments, the concentration of the aqueous solution of sodium sulfite in step B is 20%.
The inventors have found that the concentration of the aqueous sodium sulfite solution needs to be strictly controlled and must not be too high, otherwise it is easy to precipitate salts and it is difficult to separate layers.
In the preparation method of the compound II, after the reaction in the step B is completed, the post-treatment is optionally carried out. In some embodiments, the method for preparing compound II, step B post-treatment comprises: and after the reaction is finished, standing for layering, separating an upper organic phase, extracting a lower aqueous phase by using DCM, combining the organic phases, and removing the organic solvent to obtain a compound II and a compound I.
In some embodiments, the reaction described in step B completely comprises: and monitoring the compound III by using GC, wherein the reaction is complete when the content of the compound III is less than 5%.
In some embodiments, a method of preparing compound II can further comprise step C: and D, rectifying and purifying the compound II and the compound I obtained in the step B.
In some embodiments, a method of preparing compound II can further comprise step C: and C, rectifying and purifying the compound II and the compound I obtained in the step B, fully collecting at 70-100 ℃ by adopting a rectifying device with a reflux ratio controller, collecting residual solvent, collecting front fractions at the external temperature of 130-140 ℃ according to a reflux ratio of 10, wherein the front fractions are mainly diethyl malonate, the reflux ratio of 1 at 140-145 ℃ is 10, and collecting main streams which are the product compound II, namely diethyl chloropropionate, at 140-175 ℃ according to the reflux ratio of 1.
A preparation method of high-purity diethyl chloropropionate comprises the following steps:
step A: carrying out substitution reaction on the compound I and sulfonyl chloride at the reaction temperature, monitoring the reaction until the raw materials completely react, stopping the reaction, and vacuumizing excess sulfur dioxide and hydrochloric acid gas in the reaction system at the temperature of 50-80 ℃ to prepare a mixture of a compound II and a compound III;
and B, step B: reacting the compound II and the compound III obtained in the step A with a sodium sulfite aqueous solution at a reaction temperature to obtain a compound II and a compound I;
and C: and C, rectifying and purifying the compound II and the compound I obtained in the step B, fully collecting at 70-100 ℃ by adopting a rectifying device with a reflux ratio controller, and collecting residual solvent. Collecting front fractions which are mainly diethyl malonate at an external temperature of 130-140 ℃ at a reflux ratio of 10;
wherein the reaction temperature in the step A is 45-85 ℃;
the reaction temperature in the step B is 30-60 ℃; and the concentration of the sodium sulfite aqueous solution in the step B is 10-30%.
A preparation method of high-purity diethyl chloropropionate comprises the following steps:
step A: carrying out substitution reaction on the compound I and sulfonyl chloride at the temperature of 60-70 ℃, monitoring the reaction until the raw materials completely react, stopping the reaction, and vacuumizing excess sulfur dioxide and hydrogen chloride gas in a reaction system at the temperature of 50-80 ℃ to prepare a mixture of a compound II and a compound III;
and B: reacting the compound II and the compound III obtained in the step A with 15-25% of sodium sulfite aqueous solution at 40-50 ℃ to obtain a compound II and a compound I;
and C: and C, rectifying and purifying the compound II and the compound I obtained in the step B, fully collecting at 70-100 ℃ by adopting a rectifying device with a reflux ratio controller, and collecting residual solvent. Collecting front fractions mainly comprising diethyl malonate at an external temperature of 130-140 ℃ in a reflux ratio of 10.
In the technical scheme of the invention, a compound I is creatively adopted to react with sulfonyl chloride to obtain a compound II, a compound III is creatively adopted to react with a sodium sulfite aqueous solution to obtain a compound II and a raw material compound I; then rectifying and purifying by a rectifying device with controlled reflux ratio to obtain a high-purity compound II, namely chloro-diethyl malonate. Compared with the prior art, the method has the advantages that the used raw materials of sulfonyl chloride and sodium sulfite are cheap and easily available, the production cost is reduced, and the purity of the product after rectification and purification is up to 99 percent and is far higher than that of diethyl chloropropionate reported in the prior art; the method has short reaction time and shortens the production period; complex post-treatment operation is not needed in the reaction, only acid gas pumping and liquid separation extraction are involved, and the operation is simple; in the reaction, no other by-products are generated from the raw material compound I to the product compound II and a small amount of impurity compound III, and the finally rectified compound I can be recycled, so that the atom economy of the reaction is good; organic solvent is not used in the reaction, so that a large amount of waste liquid is not generated, the method is more environment-friendly, and the method is more suitable for increasingly strict environment-friendly industrial production.
In summary, the present invention includes the following beneficial effects:
1. according to the preparation method of the high-purity diethyl chloromalonate, the cheap and easily-obtained raw materials of diethyl malonate, sulfonyl chloride and sodium sulfite are adopted, so that the production cost is reduced;
2. the preparation method of the high-purity diethyl chloropropionate provided by the invention has the advantages of short reaction time, shortened production period, simplicity in operation, and capability of only pumping away acid gas and separating liquid, wherein the purity of the prepared product is up to more than 99%, and the purity is greatly improved compared with the prior art;
3. according to the preparation method of the high-purity diethyl chloropropionate, the reaction is carried out from the raw material compound I to the product compound II, and a small amount of impurity compounds III are removed, no other by-products are produced, the finally rectified compound I can be recycled, and the atom economy of the reaction is good;
4. the preparation method of the high-purity diethyl chloropropionate provided by the invention does not need to use an organic solvent, the three wastes generated are reduced, the method is more environment-friendly, and the method is more suitable for safety and environment-friendly industrial production which is stricter day by day.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound A" and "compound represented by formula A" and "formula A" means the same compound.
In the present invention, "optional" or "optionally" means that it may or may not be present; or may not be performed; the phrase "optionally adding a reaction solvent to the crude product obtained in step (C)" means that the reaction solvent may or may not be added to the crude product obtained in step (C).
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described 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, min represents minutes; h represents an hour; g represents g; ml means ml;
in the present invention, DCM denotes dichloromethane.
In the present invention, GC represents gas chromatography.
In the present invention, the concentration of the sodium sulfite aqueous solution refers to a mass concentration, specifically, a mass percentage of the sodium sulfite to the sodium sulfite aqueous solution.
In the present invention, the reaction is considered complete when the remaining amount of the raw materials does not exceed 5%, 3%, 2%, 1% or 0.5% of the charged amount in the reaction.
EXAMPLE 1 preparation of Compound II
Diethyl malonate (1 kg) was added to a 5L four-necked flask, mechanical stirring was started, and the system was warmed to 65. + -. 5 ℃. Quickly dropwise adding sulfonyl chloride (880 g), controlling the temperature at 60-72 ℃, and completing dropwise adding within 1 hour. After the dropwise addition, the reaction is carried out for 1h at 65 ℃; sampling and GC monitoring about 6 percent of raw materials, about 8 percent of dichloro impurities and about 85 percent of products, and stopping the reaction. The reaction system was at 65 ℃ and excess acid gas was removed in vacuo to yield compound II and compound III,1.2kg, 99.2% yield and 72.7% purity.
EXAMPLE 2 preparation of Compound II
The 5L four-necked flask of example 1 was further cooled to 40-50 deg.C, a 20% aqueous solution of sodium sulfite (1750 g) was added dropwise thereto, the temperature was controlled to 40-50 deg.C, and the reaction was carried out at that temperature for 1-2 hours. GC detects that the content of dichloro impurities, namely the compound III, is less than 0.5 percent, after the reaction is finished, the mixture is stood for layering, an upper organic phase is separated, a lower water phase is extracted twice by DCM (6000 mL), and the combined organic phases are directly concentrated to obtain a compound II,1260g, the yield is 105 percent, and the purity is 85.4 percent.
EXAMPLE 3 purification by distillation of Compound II
Collecting the compound II obtained by the preparation method in the embodiment 2 at 70-100 ℃, collecting residual solvent, collecting front fraction at 130-140 ℃ under a reflux ratio of 10, mainly comprising diethyl malonate, collecting cross components at 140-145 ℃ under a reflux ratio of 10:1 collecting the main flow and dividing the main flow into a product of diethyl chloropropionate. The compound II is obtained in 815g, yield 67.9% and purity 99.08%.
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 (6)
1. A preparation method of high-purity diethyl chloropropionate comprises the following steps:
step A: the compound I and sulfonyl chloride carry out substitution reaction at the reaction temperature to prepare a compound II and a compound III,
and B, step B: reacting the compound II and the compound III obtained in the step A with 10 to 30 percent of sodium sulfite aqueous solution at the temperature of between 30 and 60 ℃ to obtain a compound II and a compound I,
and C: and C, rectifying and purifying the compound II and the compound I obtained in the step B: the method comprises the following steps: the method comprises the following steps of (1) fully collecting at 70-100 ℃ by adopting a rectification device with a reflux ratio controller, collecting residual solvent, collecting front fraction at the external temperature of 130-140 ℃ according to the reflux ratio of 10.
2. The method for preparing high-purity diethyl chloromalonate according to claim 1, wherein the reaction temperature in the step A is 45-85 ℃.
3. The process for preparing high-purity diethyl chloromalonate according to claim 1, wherein in the step A, the molar ratio of the compound I to the sulfonyl chloride is 1.
4. The process for preparing high-purity diethyl chloromalonate according to claim 1, wherein in the step A, after the reaction is completed, the post-treatment is optionally performed, and the post-treatment comprises: and (3) at the temperature of between 50 and 80 ℃, vacuumizing excess sulfur dioxide and hydrogen chloride gas in the reaction system to obtain a mixture of a compound II and a compound III.
5. The process for the preparation of high-purity diethyl chloromalonate according to claim 4, wherein the reaction in step A completely comprises: the compound I is monitored by GC, and the reaction is complete when 4% -8% of the compound I remains.
6. The process for preparing high-purity diethyl chloromalonate according to claim 1, wherein in the step B, after the reaction is completed, the post-treatment is optionally performed, and comprises the following steps: standing for layering, separating an upper organic phase, extracting a lower aqueous phase with DCM, combining the organic phases, and removing the organic solvent to obtain a compound II and a compound I.
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Citations (4)
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| JPH1180035A (en) * | 1997-09-12 | 1999-03-23 | Daicel Chem Ind Ltd | Halogenating reagent and halogenation |
| JP2003335728A (en) * | 2002-05-20 | 2003-11-28 | Kanegafuchi Chem Ind Co Ltd | Method for producing 4-methylcyclopentenone derivative |
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| US4827056A (en) * | 1987-03-17 | 1989-05-02 | Kuraray Company Ltd. | Process for preparing chlorinated olefins |
| JPH1180035A (en) * | 1997-09-12 | 1999-03-23 | Daicel Chem Ind Ltd | Halogenating reagent and halogenation |
| JP2003335728A (en) * | 2002-05-20 | 2003-11-28 | Kanegafuchi Chem Ind Co Ltd | Method for producing 4-methylcyclopentenone derivative |
| CN103483166A (en) * | 2013-09-16 | 2014-01-01 | 台州职业技术学院 | Method for preparing m-anisaldehyde |
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| G. Ravi Babu et al..An Efficient and Practical Synthesis of Dimethyl 2-chloromalonate.《Scholars Research Library》.2011,第3卷(第6期),第437-442页. * |
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