CN113185473B - Preparation method of florfenicol intermediate fluoromethylsulfone oxazole - Google Patents
Preparation method of florfenicol intermediate fluoromethylsulfone oxazole Download PDFInfo
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- CN113185473B CN113185473B CN202110730789.6A CN202110730789A CN113185473B CN 113185473 B CN113185473 B CN 113185473B CN 202110730789 A CN202110730789 A CN 202110730789A CN 113185473 B CN113185473 B CN 113185473B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/20—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms
- C07C17/202—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction
- C07C17/206—Preparation of halogenated hydrocarbons by replacement by halogens of halogen atoms by other halogen atoms two or more compounds being involved in the reaction the other compound being HX
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a preparation method of florfenicol intermediate fluoromethylsulfone oxazole, wherein a adopted fluorination reagent is 1-chloro-4- (difluoromethyl) benzene, and in the preparation method, 1-chloro-4- (difluoromethyl) benzene, cyclocompound oxazoline and methylene dichloride are added, and the temperature is increased to 80-100 ℃ for reaction for 1.5-3 h. In the process, 1-chloro-4- (difluoromethyl) benzene is used as a fluorination reagent, so that a complex process of preparing the lshikawa reagent by mixing hexafluoropropylene and diethylamine for fluorination in the traditional process is omitted, and compared with the process, the preparation of the fluorination reagent of 1-chloro-4- (difluoromethyl) benzene has the advantages of high reaction speed, high conversion rate, few byproducts and the like.
Description
Technical Field
The invention relates to a method for preparing a florfenicol intermediate, belonging to the technical field of chemical synthesis.
Background
Florfenicol (Florfenicol), also known as flurprofen and Florfenicol, is an artificially synthesized veterinary-dedicated chloramphenicol spectrum antibacterial drug, which is a monofluoro derivative of thiamphenicol. The florfenicol has wide antibacterial spectrum, strong effect on gram-positive bacteria, gram-negative bacteria and mycoplasma, quick oral absorption, wide distribution, long half-life period, high blood concentration and long blood maintenance time, and is widely applied to animal husbandry, breeding industry and the like.
Patent US5382673 in 1995 discloses that D-threo-2- (2, 2-dichloro) acetamido-3-hydroxy-3-p- (methylsulfonyl) phenyl-ethyl propionate (abbreviated as D ethyl ester) is used as an initial reactant, reduced by potassium borohydride to obtain a reduced product (1R, 2R) -2-amino-1- (4- (methylsulfonyl) phenyl) -1, 3-propanediol (abbreviated as a reduced product), and cyclized by dichloroacetonitrile to obtain D-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazolemethanol (abbreviated as a cyclic oxazoline). The cyclic compound is converted into fluoromethylsulfone oxazole through the fluorination reaction of Ishikawa reagent, and finally the florfenicol and the analogues thereof are generated through hydrolysis. The yield of the Ishikawa reagent can reach 82.1% by using the process, and the preparation method of the Ishikawa reagent comprises the steps of firstly mixing diethylamine and dichloromethane, cooling to about-10 ℃, and then slowly filling hexafluoropropylene into the mixed solution to prepare the Ishikawa reagent; the fluorination reaction is to stir Ishikawa reagent at room temperature for 18 hours to mix with the cyclic compound oxazoline, to fluorinate at 100 ℃ for more than 2 hours to complete the fluorination reaction, and to obtain a florfenicol crude product through a series of solvent recovery, isopropanol hydrolysis, concentration crystallization and centrifugal separation.
Patent CN111423391A uses dichloromethane as solvent, and tetrafluoroethylene gas is introduced into dimethylamine to prepare fluorinating agent. The patent does not adopt Ishikawa fluorination reagent in the traditional process, but adopts novel tetrafluorodimethylamine fluorination reagent to carry out fluorination reaction of cyclic compound to obtain fluoromethylsulfone oxazole, thereby avoiding using hexafluoropropylene gas with higher production cost, reducing the production cost of florfenicol to a certain extent, and essentially solving the problems of complex process flow, large production energy consumption and the like in the preparation and fluorination processes of the fluorination reagent. And the final yield of the fluorination reaction by adopting the tetrafluorodimethylamine fluorinating agent is lower than that of the Ishikawa fluorinating agent, and more parts of fluorinating agent frameworks such as amide and the like are difficult to recycle after the fluorination reaction.
In patent CN111153838A, thiamphenicol is used as an initial reactant, and under the action of sulfuryl fluoride, fluoromethylsulfone oxazole is obtained through cyclization, rearrangement and dehydroxyfluorination, and florfenicol is obtained through hydrolysis. The patent uses sulfuryl fluoride as a dehydroxyfluorination reagent to replace an Ishikawa reagent used in the traditional process, and a byproduct after sulfuryl fluoride reaction is sulfuric acid, so that the generation of a large amount of amide which is difficult to recover and apply mechanically is avoided, the treatment difficulty of the byproduct is lower than that of the Ishikawa reagent, and the treatment process is mature. However, sulfuryl fluoride is toxic, has high irritation and poor safety, and the latest research shows that sulfuryl fluoride is a strong greenhouse gas and is not beneficial to environmental protection. In addition, the yield of florfenicol prepared by using sulfuryl fluoride is only medium level, the impurities contained in the florfenicol finished product are more, and the method has still not satisfactory effect.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of florfenicol intermediate fluoromethylsulfone oxazole, which realizes the following purposes:
(1) the yield and the purity of the fluoromethylsulfone oxazole are improved;
(2) the safety of the fluoro reagent is high, and a large amount of amide which is difficult to recover and reuse is avoided from the fluoro reaction;
(3) the production energy consumption is reduced, and the technological process of the fluorination reaction is shortened;
(4) the purity and the yield of the fluoro reagent are improved.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of florfenicol intermediate fluoromethylsulfone oxazole comprises the steps of adopting a fluorination reagent of 1-chloro-4- (difluoromethyl) benzene;
adding 1-chloro-4- (difluoromethyl) benzene, a cyclic oxazoline and dichloromethane, heating to 80-100 ℃ and reacting for 1.5-3 h;
the following is a further improvement of the above technical solution:
the molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the cyclic oxazoline is 2.5-3: 1.
The molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the dichloromethane is 0.12-0.15: 1.
The purity of the 1-chloro-4- (difluoromethyl) benzene is more than or equal to 98 percent.
The preparation method of the 1-chloro-4- (difluoromethyl) benzene comprises the steps of uniformly mixing p-chlorobenzylidene dichloride and antimony trichloride, removing air, introducing hydrogen fluoride gas, heating to 110-.
The reaction molar ratio of the p-chlorobenzylidene dichloride to the hydrogen fluoride is 1: 8.5-10.
Controlling the molar ratio of the p-chlorobenzylidene dichloride to the antimony trichloride to be 1: 0.048-0.052.
The preferred technical scheme is as follows:
the molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the cyclic oxazoline is 2.7-3: 1; the reaction temperature is 90-100 ℃, the reaction time is 2-3h, the molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the solvent dichloromethane is 0.13-0.15:1, the yield is 95.24-95.95.28%, and the purity is 98.77-98.82%.
The preparation method of the 1-chloro-4- (difluoromethyl) benzene is preferably as follows: the reaction molar ratio of the p-chlorobenzylidene dichloride to the hydrogen fluoride is 1: 9-10; the reaction temperature is 120-130 ℃, and the reaction time is 4-5 h; the molar ratio of the p-chlorobenzylidene dichloride to the antimony trichloride is 1: 0.05, the yield is 96-96.08 percent, and the purity is 99.8-99.83 percent.
The invention provides a preparation method of fluoromethylsulfone oxazole as a florfenicol intermediate. The method is characterized in that: 1-chloro-4- (difluoromethyl) benzene is used as a fluorinating agent to perform fluorination reaction with the cyclic compound. Because the synthesis cost of the 1-chloro-4- (difluoromethyl) benzene is high, the synthesis path is difficult, and the report that the florfenicol intermediate fluoromethanesulfone oxazole is prepared by using the 1-chloro-4- (difluoromethyl) benzene as a fluorination reagent is fresh at home and abroad, the invention adopts p-chlorobenzylidene dichloride to synthesize the 1-chloro-4- (difluoromethyl) benzene, and obtains the fluoromethanesulfone oxazole finally and simultaneously obtains the p-chlorobenzaldehyde, thereby effectively solving the problem.
The fluoromethylsulfone oxazole is named as a florfenicol intermediate (4S, 5R) -2- (1, 1-dichloromethyl) -4-fluoromethyl-5- (4-methylsulfonylphenyl) -4, 5-oxazoline;
the cyclic oxazoline is fully called as follows: d-threo-2- (dichloromethyl) -4, 5-dihydro-5- [ p- (methylsulfonyl) phenyl ] -4-oxazolemethanol;
the formula of the preparation method of the invention is as follows:
first step preparation of 1-chloro-4- (difluoromethyl) benzene fluorination reagent:
the second step of preparing fluoride oxazoline:
compared with the prior art, the technical scheme of the invention has the following beneficial effects:
(1) in addition, in the process of fluorinating the florfenicol intermediate cyclic compound by using the 1-chloro-4- (difluoromethyl) benzene, the main byproduct is p-chlorobenzaldehyde which can be used as a byproduct after separation and purification, the atom utilization rate is improved, the concept of green economic chemistry is met, the production and environmental protection cost is reduced to a greater extent, the process has a wide application prospect, and the fluorination reaction process flow is shorter.
(2) Compared with the prior art, 1-chloro-4- (difluoromethyl) benzene is used as a fluorinating agent, so that the defects of high energy consumption, high three wastes, difficult treatment of reaction byproducts and the like in the traditional process are overcome, the final yield is considerable, the molar yield of fluoromethylsulfone oxazole is 93.24-95.28%, and the purity is 98.77-98.85%; the florfenicol finished product yield is more than 90%, the energy consumption is reduced by 15%, the unit consumption is reduced by 10%, the industrial production prospect is clear, and the florfenicol finished product has the advantages of low production cost, low three wastes, low energy consumption, simple recycling of main byproducts and the like.
(3) Compared with the method that the Ishikawa reagent needs to be cooled to about minus 10 ℃ for a long time during preparation, the energy consumption is effectively reduced in the preparation process of the 1-chloro-4- (difluoromethyl) benzene fluorinating agent, the fluorinating agent has a single structure and high conversion rate, and the defect that the utilization rate of raw materials is reduced due to the combination of the byproduct hydrogen fluoride in the Ishikawa reagent and the main raw material diethylamine is overcome.
Compared with the Ishikawa reagent and cyclic compounds which can generate a large amount of Ishikawa reagent frameworks such as amides and the like which are difficult to recycle when the Ishikawa reagent and the cyclic compounds are subjected to fluorination reaction, the main byproduct of the fluorination reaction of 1-chloro-4- (difluoromethyl) benzene adopted by the invention is p-chlorobenzaldehyde, and the p-chlorobenzaldehyde can be recycled as another product.
(4) The preparation method of the 1-chloro-4- (difluoromethyl) benzene has the advantages that the yield is 93.29-96.08%, and the purity is 99.79-99.83%.
Detailed Description
The present invention will be described in further detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The first embodiment is as follows: preparation of 1-chloro-4- (difluoromethyl) benzene
Mixing 97.75g (0.5mol) of p-chlorobenzylidene dichloride and 0.7g (0.025mol) of antimony trichloride uniformly in a pressure kettle, reducing pressure to remove air in the kettle, pumping 90g (4.5mol) of hydrogen fluoride gas at room temperature, heating to 120 ℃, reacting for 4h, cooling to 40 ℃, discharging and collecting gas in the kettle, blowing the gas by using nitrogen (200 g, 7.14 mol) to be clean, cooling by deep cooling, cooling HF to liquid, absorbing the residual gas by using water, and preparing into hydrochloric acid solution. The residual mixture in the kettle is decompressed and distilled to obtain the product 1-chloro-4- (difluoromethyl) benzene, the distillate under 60-65 ℃/2.4Kpa is collected and cooled and liquefied to obtain the product colorless liquid (78g, 0.480mol), the yield is 96.01% (calculated on the basis of p-chlorobenzylidene dichloride), and the chromatographic purity is 99.80% (higher than the purity directly purchased in the market).
Example two: preparation of 1-chloro-4- (difluoromethyl) benzene
97.77g (0.5mol) of p-chlorobenzylidene dichloride and 0.7g (0.025mol) of antimony trichloride are uniformly mixed in a pressure kettle, air in the kettle is discharged under reduced pressure, 85g (4.25mol) of hydrogen fluoride gas is pumped at room temperature, the temperature is increased to 120 ℃ for reaction for 4 hours, the reaction is cooled to 40 ℃, the gas in the kettle is discharged and collected, nitrogen (200 g, 7.14 mol) is used for blowing, the HF is cooled to liquid through cryogenic cooling, and the residual gas is absorbed by water to prepare the hydrochloric acid solution. The residual mixture in the kettle is decompressed and evaporated to obtain the product 1-chloro-4- (difluoromethyl) benzene, the distillate under 60-65 ℃/2.4Kpa is collected and cooled and liquefied to obtain the product colorless liquid (75.8g, 0.466mol), the yield is 93.29% (calculated on the basis of p-chlorobenzylidene dichloride) and the chromatographic purity is 99.81%.
Example three: preparation of 1-chloro-4- (difluoromethyl) benzene
Mixing 97.75g (0.5mol) of p-chlorobenzylidene dichloride and 0.7g (0.025mol) of antimony trichloride uniformly in a pressure kettle, reducing pressure to remove air in the kettle, pumping 100g (5.0mol) of hydrogen fluoride gas at room temperature, heating to 120 ℃, reacting for 4h, cooling to 40 ℃, discharging and collecting gas in the kettle, blowing the gas by using nitrogen (200 g, 7.14 mol) to be clean, cooling by deep cooling, cooling HF to liquid, absorbing the residual gas by using water, and preparing into hydrochloric acid solution. The residual mixture in the kettle is decompressed and evaporated to obtain the product 1-chloro-4- (difluoromethyl) benzene, the distillate under the temperature of 60-65 ℃/2.4Kpa is collected and is cooled and liquefied to obtain the product colorless liquid (78.05g, 0.481mol), the yield is 96.08% (calculated on the basis of p-chlorobenzylidene dichloride), and the chromatographic purity is 99.80%.
Example four: preparation of 1-chloro-4- (difluoromethyl) benzene
97.77g (0.5mol) of p-chlorobenzylidene dichloride and 0.7g (0.025mol) of antimony trichloride are uniformly mixed in a pressure kettle, air in the kettle is discharged under reduced pressure, 90g (4.5mol) of hydrogen fluoride gas is pumped at room temperature, the temperature is increased to 110 ℃ for reaction for 4 hours, the reaction is cooled to 40 ℃, the gas in the kettle is discharged and collected, nitrogen (200 g, 7.14 mol) is used for blowing, the HF is cooled to liquid through cryogenic cooling, and the residual gas is absorbed by water to prepare the hydrochloric acid solution. The residual mixture in the kettle is decompressed and evaporated to obtain the product 1-chloro-4- (difluoromethyl) benzene, the distillate under 60-65 ℃/2.4Kpa is collected and cooled and liquefied to obtain the product colorless liquid (76.8g, 0.473mol), the yield is 94.52 percent and the chromatographic purity is 99.82 percent.
Example five: preparation of 1-chloro-4- (difluoromethyl) benzene
97.77g (0.5mol) of p-chlorobenzylidene dichloride and 0.7g (0.025mol) of antimony trichloride are uniformly mixed in a pressure kettle, air in the kettle is discharged under reduced pressure, 90g (4.5mol) of hydrogen fluoride gas is pumped at room temperature, the temperature is raised to 130 ℃ for reaction for 4 hours, the reaction is cooled to 40 ℃, the gas in the kettle is discharged and collected, nitrogen (200 g, 7.14 mol) is used for blowing, the HF is cooled to liquid through cryogenic cooling, and the residual gas is absorbed by water to prepare the hydrochloric acid solution. The residual mixture in the kettle is decompressed and evaporated to obtain the product 1-chloro-4- (difluoromethyl) benzene, the distillate under 60-65 ℃/2.4Kpa is collected and cooled and liquefied to obtain the product colorless liquid (77.98g, 0.480mol), the yield is 96.00 percent, and the chromatographic purity is 99.83 percent.
Example six: preparation of 1-chloro-4- (difluoromethyl) benzene
Mixing 97.75g (0.5mol) of p-chlorobenzylidene dichloride and 0.7g (0.025mol) of antimony trichloride uniformly in a pressure kettle, reducing pressure to remove air in the kettle, pumping 90g (4.5mol) of hydrogen fluoride gas at room temperature, heating to 120 ℃, reacting for 3.5h, cooling to 40 ℃, discharging and collecting gas in the kettle, blowing the gas by using nitrogen (200 g, 7.14 mol) to be clean, cooling HF to liquid by cryogenic cooling, absorbing the residual gas by using water, and preparing the hydrochloric acid solution. The residual mixture in the kettle is decompressed and evaporated to obtain the product 1-chloro-4- (difluoromethyl) benzene, the distillate under the temperature of 60-65 ℃/2.4Kpa is collected and is liquefied by reducing the temperature to obtain the product colorless liquid (77.01g, 0.474mol), the yield is 94.78 percent, and the chromatographic purity is 99.79 percent.
Example seven: preparation of 1-chloro-4- (difluoromethyl) benzene
Mixing 97.74g (0.5mol) of p-chlorobenzylidene dichloride and 0.7g (0.025mol) of antimony trichloride uniformly in a pressure kettle, reducing pressure to remove air in the kettle, pumping 90g (4.5mol) of hydrogen fluoride gas at room temperature, heating to 120 ℃, reacting for 5h, cooling to 40 ℃, discharging and collecting gas in the kettle, blowing the gas by using nitrogen (200 g, 7.14 mol) to be clean, cooling by deep cooling, cooling HF to liquid, absorbing the residual gas by using water, and preparing into hydrochloric acid solution. The residual mixture in the kettle is decompressed and evaporated to obtain the product 1-chloro-4- (difluoromethyl) benzene, the distillate under 60-65 ℃/2.4Kpa is collected and cooled and liquefied to obtain the product colorless liquid (78.04g, 0.48mol), the yield is 96.02 percent, and the chromatographic purity is 99.82 percent.
Example eight: preparation method of florfenicol intermediate fluoromethylsulfone oxazole
Adding prepared 1-chloro-4- (difluoromethyl) benzene (65g, 0.4mol) (prepared under the condition of example 1) and cyclic oxazoline (50g, 0.148mol) into a pressure kettle, heating solvent dichloromethane (251.4g, 2.96mol) to 90 ℃ for reaction for 2 hours, recovering dichloromethane at normal pressure after the reaction is finished, then recovering dichloromethane at reduced pressure, finally collecting fraction 1-chloro-4- (difluoromethyl) benzene of 60-65 ℃/2.4Kpa and fraction p-chlorobenzaldehyde of 80-85 ℃/2.4Kpa by adopting high vacuum degree, and separating out faint yellow solid which is fluoromethylsulfone oxazole (48g, 0.141mol) after recovery, wherein the yield is 95.27% and the chromatographic purity is 98.82%.
Example nine: preparation method of florfenicol intermediate fluoromethylsulfone oxazole
Adding the prepared 1-chloro-4- (difluoromethyl) benzene (60g, 0.37mol) (prepared under the condition of example 1) and cyclic oxazoline (50g, 0.148mol) into a pressure kettle, heating a solvent dichloromethane (251.4g, 2.96mol) to 90 ℃ for reaction for 2 hours, recovering dichloromethane at normal pressure after the reaction is finished, then recovering dichloromethane at reduced pressure, finally collecting fractions 1-chloro-4- (difluoromethyl) benzene of 60-65 ℃/2.4Kpa and fractions p-chlorobenzaldehyde of 80-85 ℃/2.4Kpa respectively by adopting high vacuum degree, and separating out faint yellow solid, namely fluoromethylsulfone oxazole (46.9g, 0.138mol), wherein the yield is 93.24% and the chromatographic purity is 98.79%.
Example ten: preparation method of florfenicol intermediate fluoromethylsulfone oxazole
The prepared 1-chloro-4- (difluoromethyl) benzene (72.28g, 0.44mol) (prepared under the condition of example 1) and cyclic oxazoline (50g, 0.148mol) are added into a pressure kettle, solvent dichloromethane (251.4g, 2.96mol) is heated to 90 ℃ for reaction for 2 hours, after the reaction is finished, dichloromethane is recovered under normal pressure and then dichloromethane is recovered under reduced pressure, finally, 60-65 ℃/2.4Kpa fraction 1-chloro-4- (difluoromethyl) benzene and 80-85 ℃/2.4Kpa fraction p-chlorobenzaldehyde are respectively collected by adopting high vacuum degree, and the separated light yellow solid after recovery is fluoromethylsulfone oxazole (47.96g, 0.131mol), the yield is 95.24%, and the chromatographic purity is 98.78%.
Example eleven: preparation method of florfenicol intermediate fluoromethylsulfone oxazole
Adding prepared 1-chloro-4- (difluoromethyl) benzene (65g, 0.4mol) (prepared under the condition of example 1) and cyclic oxazoline (50g, 0.148mol) into a pressure kettle, heating solvent dichloromethane (251.4g, 2.96mol) to 80 ℃ for reaction for 2h, recovering dichloromethane at normal pressure after the reaction is finished, then recovering dichloromethane at reduced pressure, finally collecting fraction 1-chloro-4- (difluoromethyl) benzene of 60 ℃ -65 ℃/2.4Kpa and fraction p-chlorobenzaldehyde of 80 ℃ -85 ℃/2.4Kpa by adopting high vacuum degree, and separating out faint yellow solid which is fluoromethylsulfone oxazole (47.02g, 0.138mol), wherein the yield is 93.32% and the chromatographic purity is 98.85%.
Example twelve: preparation method of florfenicol intermediate fluoromethylsulfone oxazole
Adding prepared 1-chloro-4- (difluoromethyl) benzene (65g, 0.4mol) (prepared under the condition of example 1) and cyclic oxazoline (50g, 0.148mol) into a pressure kettle, heating solvent dichloromethane (251.4g, 2.96mol) to 100 ℃ for reaction for 2 hours, recovering dichloromethane at normal pressure after the reaction is finished, then recovering dichloromethane at reduced pressure, finally collecting fraction 1-chloro-4- (difluoromethyl) benzene of 60 ℃ -65 ℃/2.4Kpa and fraction p-chlorobenzaldehyde of 80 ℃ -85 ℃/2.4Kpa by adopting high vacuum degree, and separating out faint yellow solid which is fluoromethylsulfone oxazole (48.03g, 0.141mol) after recovery, wherein the yield is 95.28%, and the chromatographic purity is 98.77%.
Example thirteen: preparation method of florfenicol intermediate fluoromethylsulfone oxazole
Adding prepared 1-chloro-4- (difluoromethyl) benzene (65g, 0.4mol) (prepared under the condition of example 1) and cyclic oxazoline (50g, 0.148mol) into a pressure kettle, heating solvent dichloromethane (251.4g, 2.96mol) to 90 ℃ for reaction for 1.5h, recovering dichloromethane at normal pressure after the reaction is finished, then recovering dichloromethane at reduced pressure, finally collecting fraction 1-chloro-4- (difluoromethyl) benzene of 60-65 ℃/2.4Kpa and fraction p-chlorobenzaldehyde of 80-85 ℃/2.4Kpa by adopting high vacuum degree, and separating out light yellow solid which is fluoromethylsulfone oxazole (47.55g, 0.139mol), wherein the yield is 94.33%, and the chromatographic purity is 98.80%.
Example fourteen: preparation method of florfenicol intermediate fluoromethylsulfone oxazole
Adding prepared 1-chloro-4- (difluoromethyl) benzene (65g, 0.4mol) (prepared under the condition of example 1) and cyclic oxazoline (50g, 0.148mol) into a pressure kettle, heating solvent dichloromethane (251.4g, 2.96mol) to 90 ℃ for reaction for 3 hours, recovering dichloromethane at normal pressure after the reaction is finished, then recovering dichloromethane at reduced pressure, finally collecting fraction 1-chloro-4- (difluoromethyl) benzene of 60-65 ℃/2.4Kpa and fraction p-chlorobenzaldehyde of 80-85 ℃/2.4Kpa respectively by adopting high vacuum degree, and separating out light yellow solid which is fluoromethylsulfone oxazole (47.98g, 0.141mol) after recovery, wherein the yield is 95.26%, and the chromatographic purity is 98.82%.
Summary of the results of the examples:
examples 1, 2 and 3 compare the molar ratio of the starting materials to p-chlorobenzylidene dichloride reacted with hydrogen fluoride and show that the molar ratio is in the range of 1: the yield is considerable when the reaction time is 9 to 10 hours.
Examples 1, 4, 5 compare the preparation temperature of 1-chloro-4- (difluoromethyl) benzene. From the yield result, the yield of 120-130 ℃ is the highest, and the yield is lower after the temperature is properly reduced, so that the chemical reaction rate is reduced, and the optimum temperature range is 120-130 ℃.
In examples 1, 6 and 7, when the reaction time in the preparation of 1-chloro-4- (difluoromethyl) benzene is compared, it can be seen that the yield is obviously reduced when the reaction time is 3.5 hours, the reaction is insufficient, the yield is not influenced by suitable extension time, and 4-5 hours is relatively suitable reaction time.
In summary, the embodiments 1, 3, 5, and 7 are preferred embodiments, and the technical solutions summarized by the preferred embodiments are as follows:
the reaction molar ratio of the p-chlorobenzylidene dichloride to the hydrogen fluoride is 1: 9-10; the reaction temperature is 120-130 ℃, and the reaction time is 4-5 h; the molar ratio of the p-chlorobenzylidene dichloride to the antimony trichloride is 1: 0.05, after the reaction is finished, cooling to 38-42 ℃, the yield is 96-96.08 percent, and the purity is 99.8-99.83 percent.
Examples 8, 9 and 10 compare the molar charge ratio of the main starting material cyclic compound for fluorination with 1-chloro-4- (difluoromethyl) benzene fluorinating agent, and show that the ratio of the two is 2.7: 1, the fluorination reaction can be completed with a considerable yield, and the raw material is wasted by increasing the molar amount of the fluorinating agent.
Examples 8, 11 and 12 compare the temperature range of the reaction of the cyclic compound with 1-chloro-4- (difluoromethyl) benzene, the reaction is sufficient at 90-100 ℃, and the yield is low and the reaction is incomplete at a low temperature.
Examples 8, 13 and 14 compare the reaction time of the cyclic compound and 1-chloro-4- (difluoromethyl) benzene, and the cyclic compound and 1-chloro-4- (difluoromethyl) benzene can be reacted completely by keeping the temperature for 2h, so that the reaction is not influenced greatly by prolonging the holding time, and the significance is low.
In summary, embodiments 8, 10, 12, and 14 are preferred embodiments, and the technical solutions obtained by the preferred embodiments are as follows:
the molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the cyclic oxazoline is 2.7-3: 1; the reaction temperature is 90-100 ℃, the reaction time is 2-3h, the molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the solvent dichloromethane is 0.13-0.15:1, the yield is 95.24-95.95.28%, and the purity is 98.77-98.82%.
Claims (7)
1. A preparation method of florfenicol intermediate fluoromethylsulfone oxazole is characterized in that: the adopted fluorinating reagent is 1-chloro-4- (difluoromethyl) benzene;
adding 1-chloro-4- (difluoromethyl) benzene, a cyclic oxazoline and dichloromethane, heating to 80-100 ℃ and reacting for 1.5-3 h;
the structural formula of the cyclic oxazoline is as follows:
the structural formula of the fluoromethylsulfone oxazole is as follows:
2. the preparation method of the florfenicol intermediate fluoromethylsulfone oxazole according to claim 1, which is characterized in that: the molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the cyclic oxazoline is 2.5-3: 1.
3. The preparation method of the florfenicol intermediate fluoromethylsulfone oxazole according to claim 1, which is characterized in that: the molar ratio of the 1-chloro-4- (difluoromethyl) benzene to the dichloromethane is 0.12-0.15: 1.
4. The preparation method of the florfenicol intermediate fluoromethylsulfone oxazole according to claim 1, which is characterized in that: the purity of the 1-chloro-4- (difluoromethyl) benzene is more than or equal to 98 percent.
5. The preparation method of the florfenicol intermediate fluoromethylsulfone oxazole according to claim 1, which is characterized in that: the 1-chloro-4- (difluoromethyl) benzene is prepared by the following method, p-chlorobenzylidene dichloride and antimony trichloride are uniformly mixed, air is removed, hydrogen fluoride gas is introduced, and the temperature is raised to 110-130 ℃ for reaction for 3.5-5 h.
6. The preparation method of florfenicol intermediate fluoromethylsulfone oxazole according to claim 5, characterized in that: the reaction molar ratio of the p-chlorobenzylidene dichloride to the hydrogen fluoride is 1: 8.5-10.
7. The preparation method of florfenicol intermediate fluoromethylsulfone oxazole according to claim 5, characterized in that: controlling the molar ratio of the p-chlorobenzylidene dichloride to the antimony trichloride to be 1: 0.048-0.052.
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