CN113214080A - Preparation process of ethyl difluorobromoacetate - Google Patents
Preparation process of ethyl difluorobromoacetate Download PDFInfo
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Abstract
The invention relates to the field of organic chemical preparation, in particular to a preparation process of ethyl difluorobromoacetate, which comprises the steps of using ethanol as a solvent and azodiisobutyronitrile as a catalyst in a reaction, using 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane as a raw material, and carrying out an oxidation reaction under the conditions of constant temperature and constant pressure by proportioning to obtain the finished product of ethyl difluorobromoacetate.
Description
Technical Field
The invention relates to the field of organic chemical preparation, in particular to a preparation process of ethyl difluorobromoacetate.
Background
Ethyl difluorobromoacetate is a colorless transparent liquid, which is an important organic synthesis intermediate. In ethyl difluorobromoacetate, the biologically active-CF is formed by substituting the bromine atom2The alpha-position fluorine of the compound is introduced into the compound, so that the electrophilicity of the carbonyl group is increased, namely the active site of the biological enzyme is increased. The fluorine atom is a bioisostere of hydroxyl groups, difluoromethylene is also known as a bioisostere of ethoxy groups, and difluoromethylene-containing compounds are effective bioactive agents. For example, with difluoromethyleneradical-CF2Substituted ethoxy groups may provide agents against HTV. And the synthesized compound can be further derived into more related compounds through the reactivity of ester bond functional groups.
In recent years, the synthesis of fluorine-containing compounds by a fluorine-containing block method has been greatly developed, and difluorobromoacetate, which contains a difluoromethylene synthesis block, is commonly used for synthesizing medicaments with a biological enzyme function, synthetic pesticides and other fluorine-containing compounds, pesticides, dye intermediates and other fluorine-containing compounds, and becomes a hot spot of domestic and foreign research. Ethyl difluorobromoacetate is a drug intermediate of gemcitabine hydrochloride, a novel anticancer drug.
Patent document CN201710799666.1 discloses a method for preparing ethyl difluorobromoacetate, relating to a method for preparing chemical reagents, which takes trichloroethylene as a raw material and comprises the following steps: under the action of catalytic medium ultraviolet light, trichloroethylene reacts with oxygen in a reactor for oxidation reaction to synthesize dichloroacetyl chloride; the dichloroacetyl chloride and diethylamine are aminated under the action of catalyst to synthesize dichloroacetyl diethylamine; performing a fluoro reaction on dichloroacetyl diethylamine and anhydrous potassium fluoride in a solvent and a phase transfer catalyst to synthesize difluoroacetyl diethylamine; esterifying difluoroacetyldiethylamine to synthesize ethyl difluoroacetate; and (3) brominating the ethyl difluoroacetate by using copper bromide as a brominating agent to obtain the finished product ethyl difluorobromoacetate.
From the above documents, alkyl halide or halogenated olefin is used as raw material, under the action of ultraviolet light or catalyst, difluorobromoacetyl halide is prepared, and finally, the desired product is obtained by esterification. Only the use of sulfur trioxide or sulfuric acid, which are corrosive reaction media, is required, more or less, catalysts (such as copper salts and mercury salts) harmful to the environment are required, or volatile and corrosive gases (such as hydrogen chloride and hydrogen fluoride) are generated, so that special and expensive equipment (such as PVDF or PTFE spraying) is required, and on the other hand, a complicated treatment process is required when waste gas is treated, and special equipment is required when the treatment is difficult or dangerous; because the yield of the reaction is relatively low, the generation of dangerous waste is high.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to solve the technical problems that no corrosive solvent is needed in the synthesis of ethyl difluorobromoacetate, corrosive gas is avoided, and the environment is more friendly and safer by using ethanol as a solvent and azodiisobutyronitrile as a catalyst in the reaction, taking 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane as a raw material and carrying out oxidation reaction under the conditions of constant temperature and constant pressure according to the proportion to prepare the finished ethyl difluorobromoacetate.
Aiming at the technical problems, the technical scheme is as follows:
a process for preparing ethyl difluorobromoacetate comprises
Step one, feeding: adding 280kg of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane, 600-1000kg of absolute ethyl alcohol and 0.5kg of azodiisobutyronitrile into an enamel reaction kettle with a tail gas treatment system and a condenser;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, maintaining the pressure at 0.1-0.2 MPa, keeping the micro-reflux state, continuously reacting for 6-24 hours, and adding 0-0.5 kg of azodiisobutyronitrile again in the process;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: transferring the distillation residue to a distillation packed tower rectifying still with the volume of not less than 6 meters, and carrying out vacuum rectification to obtain a fraction of 57-58 ℃/100mmHg, namely ethyl difluorobromoacetate.
Further, 1kmol of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane was added in the first step.
Further, according to the steps, 695kg of absolute ethyl alcohol is added in the first step, the pressure in the kettle is kept at 0.1MPa in the second step, and the reaction is continued for 11-13 hours in a micro-reflux state under the condition of keeping the reaction temperature and the reaction pressure, so that 182.7kg of ethyl difluorobromoacetate can be obtained, the content is 99.0%, and the yield is 88.81%.
Further, according to the steps, 695kg of absolute ethyl alcohol is added in the first step, the pressure in the kettle is kept at 0.1MPa in the second step, the micro-reflux state is kept for continuous reaction for 5-7 hours under the condition of keeping the reaction temperature and the reaction pressure, then 0.5kg of azobisisobutyronitrile is added again, the micro-reflux state is kept for continuous reaction for 5-7 hours under the condition of keeping the same reaction temperature and the same reaction pressure, and 186.7kg of ethyl difluorobromoacetate with the content of 99.0% and the yield of 90.76% can be obtained.
Further, according to the steps, 920kg of absolute ethyl alcohol is added in the first step, the pressure in the kettle is kept at 0.2MPa in the second step, and the reaction is continued for 11-13 hours in a micro-reflux state under the condition of keeping the reaction temperature and the reaction pressure, so that 184.0kg of ethyl difluorobromoacetate can be obtained, the content is 99.1%, and the yield is 89.83%.
Further, according to the steps, 920kg of absolute ethyl alcohol is added in the first step, the pressure in the kettle is kept at 0.2MPa in the second step, the micro-reflux state is kept for continuous reaction for 11-13 hours under the condition of keeping the reaction temperature and the reaction pressure, then 0.5kg of azobisisobutyronitrile is added again, the micro-reflux state is kept for continuous reaction for 11-13 hours under the condition of keeping the same reaction temperature and the same reaction pressure, and 181.0kg of ethyl difluorobromoacetate, the content of which is 99.0 percent, and the yield of which is 87.98 percent can be obtained.
The invention has the beneficial effects that:
(1) according to the invention, ethanol is used as a solvent and azodiisobutyronitrile is used as a catalyst in the reaction, 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is used as a raw material, and the finished product of ethyl difluorobromoacetate is prepared by performing oxidation reaction at constant temperature and constant pressure according to a ratio, so that a corrosive solvent is not needed in the synthesis of ethyl difluorobromoacetate, corrosive gas is avoided, and the ethyl difluorobromoacetate is more environment-friendly and safer;
(2) the invention avoids corrosive gas in the reaction process, thereby reducing the requirement on equipment, and can utilize common glass lining reaction equipment, reduce the production investment and cost and be more beneficial to the mass production of products.
In conclusion, the method has the advantages of high product yield, more environment-friendly property and safety, and is particularly suitable for the field of organic chemical preparation.
Drawings
FIG. 1 is a schematic view of the process of the present invention;
FIG. 2 is a schematic flow chart of an embodiment of the present invention;
FIG. 3 is a schematic diagram of a three-flow process according to an embodiment of the present invention;
FIG. 4 is a schematic flow chart of a fourth embodiment of the present invention;
fig. 5 is a schematic flow chart of an embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the description of the present invention, it is to be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", and the like, indicate orientations and positional relationships based on those shown in the drawings, and are used only for convenience of description and simplicity of description, and do not indicate or imply that the equipment or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus, should not be considered as limiting the present invention.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the 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.
Example one
As shown in figure 1, a preparation process of ethyl difluorobromoacetate comprises
Step one, feeding: 280kg of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane, 600 kg of absolute ethyl alcohol and 0.5kg of azobisisobutyronitrile are added into a 2000-liter enamel reaction kettle with a tail gas treatment system and a condenser with a cooling area of 10 square meters;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, maintaining the pressure at 0.1-0.2 MPa, keeping the micro-reflux state, continuously reacting for 6-24 hours, and adding 0-0.5 kg of azodiisobutyronitrile again in the process;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: and transferring the distillation residue to a rectifying still with ≧ 6 meters of distillation packing tower for vacuum rectification to obtain a fraction of 57-58 ℃/100mmHg, namely ethyl difluorobromoacetate.
Example two
As shown in fig. 2, the second embodiment is different from the first embodiment in that:
step one, feeding: 280kg (1.0kmol) of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane and 695kg of absolute ethanol, and 0.5kg of azobisisobutyronitrile were added to a 2000-liter enamel reactor having a tail gas treatment system and a condenser with a cooling area of 10 m square;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, maintaining the pressure at 0.1MPa, and continuously reacting for 11-13 hours under a micro-reflux state;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: transferring the distillation residue to a rectifying still with a distillation packing tower with the diameter of being not less than 6 meters, and carrying out vacuum rectification to obtain a fraction with the temperature of 57-58 ℃/100mmHg, so that 182.7kg of ethyl difluorobromoacetate can be obtained, the content of the ethyl difluorobromoacetate is 99.0%, and the yield of the ethyl difluorobromoacetate is 88.81%.
EXAMPLE III
As shown in fig. 3, the third embodiment is different from the second embodiment in that:
step one, feeding: 280kg (1.0kmol) of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane and 695kg of absolute ethanol, and 0.5kg of azobisisobutyronitrile were added to a 2000-liter enamel reactor having a tail gas treatment system and a condenser with a cooling area of 10 m square;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, keeping the pressure at 0.1MPa, keeping the micro-reflux state, continuously reacting for 5-7 hours, adding 0.5kg of azodiisobutyronitrile again, keeping the same reaction temperature and pressure, and keeping the micro-reflux state, and continuously reacting for 5-7 hours;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: transferring the distillation residue to a rectifying still with at least 6 meters of distillation packing tower, and carrying out vacuum rectification to obtain 57-58 ℃/100mmHg fractions, so that 186.7kg of ethyl difluorobromoacetate can be obtained, the content is 99.0%, and the yield is 90.76%.
Example four
As shown in fig. 4, the fourth embodiment is different from the third embodiment in that:
step one, feeding: 280kg (1.0kmol) of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane and 920kg of absolute ethyl alcohol and 0.5kg of azobisisobutyronitrile are added into a 2000 liter enamel reaction kettle with a tail gas treatment system and a condenser with a cooling area of 10 square meters;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, maintaining the pressure at 0.2MPa, and continuously reacting for 11-13 hours under a micro-reflux state;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: transferring the distillation residue to a distillation tower with a distillation packing size of not less than 6 meters, and carrying out vacuum rectification to obtain a fraction of 57-58 ℃/100mmHg, thus obtaining 184.0kg of ethyl difluorobromoacetate with the content of 99.1% and the yield of 89.83%.
EXAMPLE five
As shown in fig. 5, the fifth embodiment is different from the fourth embodiment in that:
step one, feeding: 280kg (1.0kmol) of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane and 920kg of absolute ethyl alcohol and 0.5kg of azobisisobutyronitrile are added into a 2000 liter enamel reaction kettle with a tail gas treatment system and a condenser with a cooling area of 10 square meters;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, keeping the pressure at 0.2MPa, keeping the micro-reflux state, continuously reacting for 11-13 hours, adding 0.5kg of azodiisobutyronitrile again, keeping the same reaction temperature and pressure, and keeping the micro-reflux state, and continuously reacting for 11-13 hours;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: transferring the distillation residue to a rectifying still with a distillation packing tower with the diameter of being not less than 6 meters, and carrying out vacuum rectification to obtain a fraction with the temperature of 57-58 ℃/100mmHg, thus obtaining 181.0kg of ethyl difluorobromoacetate with the content of 99.0% and the yield of 87.98%.
Comparative example
1. Adding 400kg of absolute ethyl alcohol into a 1000-liter esterification kettle, starting stirring, opening a kettle jacket, and cooling chilled water to below 0 ℃;
2. adding 1000kg of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane into a 1000-liter acylation kettle, starting stirring, opening a kettle jacket to freeze saline water, cooling the kettle to below 30 ℃, adding 5kg of mercury sulfate and adding 180kg of concentrated sulfuric acid; then 1000kg of fuming sulfuric acid is added into an acylation kettle, and the temperature in the kettle gradually rises along with the reaction;
3. the liquid reflux amount in the acylation kettle is gradually increased, when the temperature rises quickly, the chilled water is opened for cooling, the pressure is relieved to ensure that the acylate, namely the difluorobromoacetyl halide passes through a condenser and then enters the esterification kettle through a low-boiling-point material receiving groove for reaction to generate an ethanol solution of the difluorobromoethyl acetate, then the ethanol solution is transferred to a distillation kettle, the ethanol is evaporated at normal pressure, the distillation residue is transferred to a distillation kettle at least with a 6-meter distillation packed tower for distillation to obtain 501kg of the difluorobromoethyl acetate, the content is 99.1 percent, and the yield is 68.26 percent
The working process is as follows:
step one, feeding: 280kg of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane, 600 kg of absolute ethyl alcohol and 0.5kg of azobisisobutyronitrile are added into a 2000-liter enamel reaction kettle with a tail gas treatment system and a condenser with a cooling area of 10 square meters;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, maintaining the pressure at 0.1-0.2 MPa, keeping the micro-reflux state, continuously reacting for 6-24 hours, and adding 0-0.5 kg of azodiisobutyronitrile again in the process;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: and transferring the distillation residue to a rectifying still with ≧ 6 meters of distillation packing tower for vacuum rectification to obtain a fraction of 57-58 ℃/100mmHg, namely ethyl difluorobromoacetate.
In the description of the present invention, it is to be understood that the terms "front-back", "left-right", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the referred device or component must have a specific orientation, be constructed in a specific orientation, and be operated, and thus should not be construed as limiting the invention.
Of course, in this disclosure, those skilled in the art will understand that the terms "a" and "an" should be interpreted as "at least one" or "one or more," i.e., in one embodiment, a number of an element may be one, and in another embodiment, a number of the element may be plural, and the terms "a" and "an" should not be interpreted as limiting the number.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily made by those skilled in the art in light of the technical teaching of the present invention should be included within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (6)
1. A preparation process of ethyl difluorobromoacetate is characterized by comprising
Step one, feeding: adding 280kg of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane, 600-1000kg of absolute ethyl alcohol and 0.5kg of azodiisobutyronitrile into an enamel reaction kettle with a tail gas treatment system and a condenser;
step two, heating for constant pressure and continuously reacting: introducing oxygen to a constant pressure, slowly heating to reflux, maintaining the pressure at 0.1-0.2 MPa, keeping the micro-reflux state, continuously reacting for 6-24 hours, and adding 0-0.5 kg of azodiisobutyronitrile again in the process;
step three, tracking, sampling and analyzing: sampling, tracking and analyzing the reactants in the kettle, and stopping the reaction when the content of the 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is less than or equal to 0.5%;
step four, removing ethanol: transferring the reaction solution to a distillation kettle, and distilling off ethanol at normal pressure;
step five, rectification: and transferring the distillation residue to a distillation packed tower rectifying still with at least 6 meters for vacuum rectification to obtain a distillate with the temperature of 57-58 ℃/100mmHg, namely ethyl difluorobromoacetate.
2. The process of claim 1, wherein 1kmol of 1-chloro-1, 2-dibromo-1, 2, 2-trifluoroethane is added in the first step.
3. The process for preparing ethyl difluorobromoacetate according to claim 2, wherein 695kg of anhydrous ethanol is added in the first step, the pressure in the kettle is kept at 0.1MPa in the second step, and the reaction is continued for 11-13 hours in a micro-reflux state under the condition of keeping the reaction temperature and pressure, so that 182.7kg of ethyl difluorobromoacetate can be obtained, the content of the ethyl difluorobromoacetate is 99.0%, and the yield of the ethyl difluorobromoacetate is 88.81%.
4. The process for preparing ethyl difluorobromoacetate according to claim 2, wherein 695kg of anhydrous ethanol is added in the first step, the pressure in the kettle is kept at 0.1MPa in the second step, the micro-reflux state is kept for reaction for 5-7 hours under the condition of keeping the reaction temperature and pressure, then 0.5kg of azobisisobutyronitrile is added again, and the micro-reflux state is kept for reaction for 5-7 hours under the condition of keeping the same reaction temperature and pressure, so that 186.7kg of ethyl difluorobromoacetate can be obtained, the content is 99.0%, and the yield is 90.76%.
5. The preparation process of ethyl difluorobromoacetate as claimed in claim 2, wherein 920kg of absolute ethanol is added in the first step, the pressure in the kettle is kept at 0.2MPa in the second step, and the reaction is continued for 11-13 hours in a micro-reflux state under the condition of keeping the reaction temperature and pressure, so that 184.0kg of ethyl difluorobromoacetate can be obtained, the content is 99.1%, and the yield is 89.83%.
6. The process for preparing ethyl difluorobromoacetate according to claim 2, wherein 920kg of absolute ethanol is added in the first step, the pressure in the kettle is kept at 0.2MPa in the second step, the micro-reflux state is kept for reaction for 11-13 hours under the condition of keeping the reaction temperature and pressure, then 0.5kg of azobisisobutyronitrile is added again, and the micro-reflux state is kept for reaction for 11-13 hours under the condition of keeping the same reaction temperature and pressure, so that 181.0kg of ethyl difluorobromoacetate can be obtained, the content is 99.0%, and the yield is 87.98%.
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US4150067A (en) * | 1975-02-13 | 1979-04-17 | Institut Francais Du Petrole | Metal-containing polymers, their manufacture and use |
CN1131659A (en) * | 1994-12-05 | 1996-09-25 | 埃尔夫阿托化学有限公司 | Process for preparation of alkyl halodifluoroacetates |
JPH1180084A (en) * | 1997-07-15 | 1999-03-23 | Kanto Denka Kogyo Co Ltd | Production of bromodifluoroacetic ester |
CN106397186A (en) * | 2016-08-31 | 2017-02-15 | 河北正朗制药有限公司 | Preparation method of ethyl bromodifluoroacetate |
CN112079721A (en) * | 2020-09-16 | 2020-12-15 | 南通宝凯药业有限公司 | Production process of ethyl difluorobromoacetate |
-
2021
- 2021-05-17 CN CN202110532235.5A patent/CN113214080A/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US4150067A (en) * | 1975-02-13 | 1979-04-17 | Institut Francais Du Petrole | Metal-containing polymers, their manufacture and use |
CN1131659A (en) * | 1994-12-05 | 1996-09-25 | 埃尔夫阿托化学有限公司 | Process for preparation of alkyl halodifluoroacetates |
JPH1180084A (en) * | 1997-07-15 | 1999-03-23 | Kanto Denka Kogyo Co Ltd | Production of bromodifluoroacetic ester |
CN106397186A (en) * | 2016-08-31 | 2017-02-15 | 河北正朗制药有限公司 | Preparation method of ethyl bromodifluoroacetate |
CN112079721A (en) * | 2020-09-16 | 2020-12-15 | 南通宝凯药业有限公司 | Production process of ethyl difluorobromoacetate |
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