CN111978218A - Synthetic method of florfenicol - Google Patents

Synthetic method of florfenicol Download PDF

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CN111978218A
CN111978218A CN201910438274.1A CN201910438274A CN111978218A CN 111978218 A CN111978218 A CN 111978218A CN 201910438274 A CN201910438274 A CN 201910438274A CN 111978218 A CN111978218 A CN 111978218A
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florfenicol
waste liquid
compound
another preferred
reaction
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朱文峰
郭朋
黄嘉慧
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Shanghai Vastpro Technology Development Co ltd
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Shanghai Vastpro Technology Development Co ltd
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Priority to CN201910438274.1A priority Critical patent/CN111978218A/en
Priority to PCT/CN2020/091701 priority patent/WO2020238779A1/en
Priority to CN202080038005.7A priority patent/CN113874351B/en
Publication of CN111978218A publication Critical patent/CN111978218A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F9/00—Multistage treatment of water, waste water or sewage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/001—Processes for the treatment of water whereby the filtration technique is of importance
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
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    • C02F1/02—Treatment of water, waste water, or sewage by heating
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2101/00—Nature of the contaminant
    • C02F2101/10—Inorganic compounds
    • C02F2101/12—Halogens or halogen-containing compounds
    • C02F2101/14—Fluorine or fluorine-containing compounds
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2101/00—Nature of the contaminant
    • C02F2101/30—Organic compounds
    • C02F2101/36—Organic compounds containing halogen
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2103/00—Nature of the water, waste water, sewage or sludge to be treated
    • C02F2103/34—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32
    • C02F2103/343—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32 from the pharmaceutical industry, e.g. containing antibiotics
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2103/00—Nature of the water, waste water, sewage or sludge to be treated
    • C02F2103/34—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32
    • C02F2103/36—Nature of the water, waste water, sewage or sludge to be treated from industrial activities not provided for in groups C02F2103/12 - C02F2103/32 from the manufacture of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton

Abstract

The invention relates to a florfenicol synthesis method, which comprises the following steps: sulfuryl fluoride is used as a fluorinating reagent to fluorinate the compound I to obtain a product, and the product is subjected to ring-opening reaction in a water-containing system, so that the florfenicol can be simply and conveniently prepared. The method has the advantages of simple operation, few byproducts, safety, environmental protection, low production cost and the like, and is very suitable for industrial use.

Description

Synthetic method of florfenicol
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a synthesis method of florfenicol.
Background
Florfenicol (Florfenicol), also known as flurprofen, Florfenicol and the like, is a 3-position fluorine derivative of thiamphenicol in broad-spectrum antifungal drugs of chloramphenicol, and is mainly used for preventing and treating animal diseases, treating systemic infection of livestock, poultry and aquatic animals and the like. In recent years, the production and export of florfenicol in China are increasing, and the florfenicol is listed in a variety list with the annual export amount of more than 1 hundred million dollars of pharmaceutical raw materials in China, and attracts attention.
Florfenicol is chemically known as 2, 2-dichloro-N- ((1R,2S) -3-fluoro-1-hydroxy-1- (4- (methylsulfonyl) phenyl) propan-2-yl) acetamide, and has the following chemical structural formula:
Figure BDA0002071245520000011
At present, florfenicol production process routes of various domestic manufacturers are consistent, and D-p-methylsulfonylphenylserine ethyl ester is used as a raw material, and is subjected to reduction, cyclization, fluorination and hydrolysis to obtain a florfenicol raw material medicament.
Figure BDA0002071245520000012
Wherein, the step of fluorinating adopts Ishikawa reagent fluorination method to perform fluorination. The fluorinating agent accounts for about 15% of the total material cost, the actual process consumption is 1.5 times of the theoretical amount of chemical reaction, and the theoretical utilization rate of fluorine atoms is only one sixth, so that a large amount of fluorine-containing substances are waste. Moreover, Ishikawa reagent (N, N-diethyl-1, 1,2,3,3, 3-hexafluoropropylamine) is converted into by-products N, N-diethyl-2, 3,3, 3-tetrafluoropropionamide and fluoride ions after a fluorination reaction, wherein the N, N-diethyl-2, 3,3, 3-tetrafluoropropionamide is difficult to recycle, and fluorine-containing wastewater of the N, N-diethyl-2, 3, 3-tetrafluoropropionamide can not reach the discharge standard, and the poisoning effect on a wastewater treatment system is very serious. In addition, due to the stability of Ishikawa reagent, the existing preparation method is usually adopted in factory production, and the production process of the reagent needs conditions of ultralow temperature, high pressure, high temperature and the like, so that the energy consumption and the safety risk are increased.
With the increasing demand of florfenicol in the market, the development of a new florfenicol synthesis process method for reducing the cost of the existing production process and avoiding the process route with serious pollution and the reaction with potential danger have very important economic and social meanings.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a simpler, more environment-friendly and more economical synthesis method of florfenicol suitable for industrialization.
In order to achieve the purpose, the invention provides the following technical scheme:
in a first aspect of the present invention, there is provided a method for preparing florfenicol, comprising the steps of:
Figure BDA0002071245520000021
(1) carrying out fluorination reaction on the compound I and a fluorinating agent in an inert solvent in the presence of an organic base to obtain a reaction mixture containing a compound II; the fluorinating reagent is sulfuryl fluoride;
(2) and (3) carrying out ring opening reaction on the reaction mixture containing the compound II obtained in the previous step in an aqueous system to obtain the florfenicol.
In another preferred embodiment, in step (1), the inert solvent is selected from the group consisting of: acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, or combinations thereof.
In another preferred embodiment, in step (1), the ratio of the amount of compound I to the inert solvent is 1 kg: 5-15 kg or L; preferably 1 kg: 7-10 kg or L.
In another preferred example, in the step (1), the amount of the fluorinating agent is 1-2.0 times of that of the compound I.
In another preferred embodiment, the amount of the fluorinating agent is 1-1.5 times of that of the compound I.
In another preferred embodiment, in step (1), the organic base is selected from the group consisting of: triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, or a combination thereof.
In another preferred example, in the step (1), the amount of the organic base is 1 to 1.5 times that of the compound I.
In another preferred example, in the step (1), the amount of the organic base is 1.2 to 1.5 times that of the compound I.
In another preferred example, in the step (1), the temperature of the fluorination reaction is-15 to 30 ℃; preferably-15 to 0 degrees.
In another preferred embodiment, in the step (1), the fluorination reaction is carried out under a system pressure of 1 to 3 atmospheres, or 1 to 2 atmospheres, or 2 to 3 atmospheres.
In another preferred example, in the step (1), the time of the fluorination reaction is 1 to 24 hours.
In another preferred example, in the step (1), after the fluorination reaction is completed, the reaction mixture is concentrated, and the concentrated reaction mixture is used in the step (2) without separation, which is a reaction mixture containing the compound II.
In another preferred embodiment, in step (2), the aqueous system is a mixture of C1-6 alkyl alcohol and water.
In another preferred example, the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.
In another preferred embodiment, the volume usage (liter) of the aqueous system is 5-10 times the weight usage (kilogram) of compound I; preferably 7-8 times.
In another preferred embodiment, the content of water in the aqueous system is 20% to 40%.
In another preferred embodiment, in the aqueous system, the content of water is 20-30%; more preferably, the water content is 25% to 30%.
In another preferred example, in the step (2), the temperature of the ring-opening reaction is 60 to 100 ℃.
In another preferred example, the temperature of the ring-opening reaction is 80-85 ℃.
In another preferred example, in the step (2), the ring-opening reaction time is 1 to 10 hours; preferably 2 to 4 hours.
In another preferred example, in the step (2), after the ring-opening reaction is finished, the reaction mixture is filtered, and the solid is collected to be florfenicol.
In another preferred example, in the step (2), after the ring-opening reaction is finished and before the filtering, the reaction mixture after the reaction is finished is cooled (for example, to 0 to 10 degrees).
In another preferred example, after the step (2), the method further comprises a step (3): and (3) recrystallizing the florfenicol obtained in the step (2) in a water-containing system, filtering after crystallization, and collecting solids to obtain the purified florfenicol.
In another preferred embodiment, the aqueous system is a mixture of a C1-6 alkyl alcohol and water.
In another preferred example, the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol or tert-butanol.
In another preferred embodiment, in the aqueous system, the content of water is 20-40%; preferably 25% to 30%.
In another preferred embodiment, the volume usage (liter) of the aqueous system is 5-10 times the weight usage (kilogram) of compound I; preferably 7-8 times.
In another preferred embodiment, the recrystallization comprises the steps of: firstly, the florfenicol family obtained in the step (2) is dissolved, and then the temperature is reduced, and standing and crystallization are carried out.
In another preferred example, the cooling includes: firstly, cooling to 20-25 ℃; then the temperature is reduced to 5-10 ℃.
In another preferred embodiment, the purified florfenicol obtained in step (3) meets the drug sales code standards of the people's republic of China.
In another preferred example, after the step (2) and/or the step (3), a waste liquid treatment step (4) is further included: and heating and refluxing the waste liquid obtained by the preparation method and a sodium hydroxide aqueous solution, and converting fluorine atoms in the waste liquid into fluorine ions.
In another preferred embodiment, the sodium hydroxide aqueous solution is 5 to 20 weight percent of sodium hydroxide aqueous solution; preferably 5% -15% aqueous sodium hydroxide solution.
In another preferred example, the weight of the sodium hydroxide aqueous solution is equivalent to the weight of the waste liquid obtained in the previous step.
In another preferred embodiment, the heating reflux treatment is performed for 1 to 10 hours; preferably 1 to 8 hours; more preferably 3-6 hours.
In another preferred example, step (5) is included after step (4); and (4) treating the waste liquid treated in the step (4) by lime water, and filtering to obtain filtrate which reaches the discharge standard of an industrial park.
In another preferred example, the weight of the lime water is equivalent to that of the waste liquid obtained in the previous step.
In another preferred example, the discharge standard of the industrial park is met, namely the content of fluorinion in the filtrate is less than or equal to 10 ppm.
In another preferred example, the waste liquid obtained by the preparation method in the step (4) is the filtrate obtained in the step (2) and/or the step (3).
In a second aspect, the present invention provides a method for treating a waste liquid produced by the production method of the first aspect; the method comprises the following steps: heating and refluxing the waste liquid and a sodium hydroxide aqueous solution to convert fluorine atoms into fluorine ions; then the waste liquid is treated by lime water, thus forming the waste liquid which reaches the discharge standard of the industrial park.
In another preferred embodiment, the sodium hydroxide aqueous solution is 5 to 20 weight percent of sodium hydroxide aqueous solution; preferably 5% -15% aqueous sodium hydroxide solution.
In another preferred example, the weight of the sodium hydroxide aqueous solution is equivalent to the weight of the waste liquid obtained in the previous step.
In another preferred embodiment, the heating reflux treatment is performed for 1 to 10 hours; preferably 1 to 8 hours; more preferably 3-6 hours.
In another preferred example, the weight of the lime water is equivalent to that of the waste liquid obtained in the previous step.
In another preferred example, the content of fluorinion in the waste liquid meeting the discharge standard of the industrial park is less than or equal to 10 ppm.
Compared with the existing method, the synthesis method disclosed by the invention has the advantages of simplicity in operation, few byproducts, safety, environmental friendliness, low production cost and the like, and is suitable for industrial production.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor has long and intensive research and unexpectedly found a florfenicol production method which is very suitable for industrialization, wherein sulfuryl fluoride is used as a fluorinating reagent to fluorinate a compound I, and after the reaction is finished, a fluorination product can be put into a ring-opening reaction without additional purification and separation, so that the florfenicol is obtained. In particular, the post-treatment of the waste liquid generated by the production method is very simple and convenient, and the waste liquid can reach the discharge standard in the industry only by using sodium hydroxide and lime water in sequence. And the fluoro reagent has stable source and low cost, can greatly reduce the cost of the fluorination reaction, correspondingly greatly reduces the synthesis cost of the florfenicol, and is very suitable for industrialization. On this basis, the inventors have completed the present invention.
The invention provides a preparation method of florfenicol, which comprises the following steps:
Figure BDA0002071245520000061
(a) in an inert solvent, in the presence of organic base, carrying out fluorination reaction on a compound I and sulfuryl fluoride, after the fluorination reaction is finished, concentrating a reaction mixture, and collecting a concentrate, wherein the concentrate is directly used in the next step without any separation and purification steps;
(b) and (3) carrying out ring opening reaction on the concentrate obtained in the previous step in an aqueous system to obtain the florfenicol.
In another preferred embodiment, in step (a), the ratio of the amount of compound I to the inert solvent is 1 kg: 5-15 kg or L; preferably 1 kg: 7-10 kg or L.
In another preferred embodiment, in step (a), the inert solvent is selected from the group consisting of: acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, or combinations thereof.
In another preferred example, in the step (a), the amount of the fluorinating agent is 1-2.0 times of that of the compound I; preferably 1 to 1.5 times.
In another preferred embodiment, in step (a), the organic base is selected from the group consisting of: triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, or a combination thereof.
In another preferred example, in the step (a), the amount of the organic base is 1-1.5 times that of the compound I; preferably 1.2 to 1.5 times.
In another preferred example, in the step (a), the temperature of the fluorination reaction is-15 to 30 ℃; preferably-15 to 0 degrees.
In another preferred embodiment, in the step (a), the fluorination reaction is carried out under a system pressure of 1 to 3 atmospheres, or 1 to 2 atmospheres, or 2 to 3 atmospheres.
In another preferred embodiment, in the step (a), the time of the fluorination reaction is 1 to 24 hours.
In another preferred embodiment, in step (b), the aqueous system is a mixture of C1-6 alkyl alcohol and water.
In another preferred example, the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol or tert-butanol.
In another preferred embodiment, in the aqueous system, the content of water is 20-40%; more preferably, the water content is 25% to 30%.
In another preferred example, in the step (b), the temperature of the ring-opening reaction is 60 to 100 ℃; preferably 80-85 degrees.
In another preferred example, in the step (b), the ring-opening reaction time is 1 to 10 hours; preferably 2 to 4 hours.
In another preferred embodiment, in step (b), after the ring-opening reaction is completed, the reaction mixture is filtered, and the solid is collected as florfenicol.
In another preferred example, in the step (b), after the ring-opening reaction is finished and before the filtering, the reaction mixture after the reaction is finished is cooled (for example, to 0 to 10 degrees).
In another preferred embodiment, after step (b), further comprising step (c): recrystallizing the florfenicol obtained in the step (b) in a water-containing system, filtering after crystallization, and collecting solids so as to obtain the purified florfenicol.
In another preferred embodiment, the aqueous system is a mixture of a C1-6 alkyl alcohol and water.
In another preferred example, the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol or tert-butanol.
In another preferred embodiment, in the aqueous system, the content of water is 20-40%; preferably 25% to 30%.
In another preferred embodiment, the recrystallization comprises the steps of: firstly, the florfenicol family obtained in the step (2) is dissolved, and then the temperature is reduced, and standing and crystallization are carried out.
In another preferred example, the cooling includes: firstly, cooling to 20-25 ℃; then the temperature is reduced to 5-10 ℃.
In another preferred embodiment, the purified florfenicol obtained in step (c) meets the national drug sales code standards.
The invention also provides a method for treating the waste liquid.
The treatment method of the waste liquid comprises the following steps of sodium hydroxide treatment: and heating and refluxing the waste liquid and a sodium hydroxide aqueous solution, so that all fluorine atoms in the waste liquid are converted into fluorine ions.
After the treatment of sodium hydroxide, all fluorine atoms in the waste liquid are converted into fluorine ions of sodium fluoride, and the fluorine ions and the sodium ions form the sodium fluoride. The sodium fluoride can be recycled.
The treatment method of the waste liquid also comprises a lime water treatment step: and (3) treating the waste liquid treated by the sodium hydroxide obtained in the step (a) by using lime water, and filtering to form the waste liquid meeting the discharge standard of an industrial park.
In another preferred example, the content of fluorinion in the waste liquid meeting the discharge standard of the industrial park is less than or equal to 10 ppm.
The waste liquid may be the filtrate obtained in step (b) and/or step (c).
The waste liquid contains the compound salt of fluorosulfonic acid and organic base and excessive sulfuryl fluoride.
Figure BDA0002071245520000081
The main advantages of the invention are:
in the preparation method, sulfuryl fluoride is used as a fluorinating reagent, an additional fluorine source is not needed, the utilization rate of fluorine atoms is high, and the utilization rate can reach 50%. The fluorizating reagent is a fumigant sulfuryl fluoride which is widely applied, has stable source and low cost, and the consumption of the fluorizating reagent is small, so the cost of the fluorizating reagent is reduced by more than 50 percent.
In the preparation method, the reaction of each step does not need harsh operations such as ultralow temperature, high pressure and the like, and complex post-treatment is not needed between the steps. The method is safer, more economical and simpler.
The preparation method of the invention has high reaction yield and the product quality meets the standard.
More importantly, in the preparation method, the byproduct is single, and fluorine atoms in the waste liquid can be completely converted into recoverable fluorine ions after simple treatment. Moreover, the waste liquid can reach the discharge standard of an industrial park through simple treatment. Therefore, the method is more environment-friendly.
In conclusion, the method of the invention is very suitable for being used as an industrial production method of florfenicol.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Equivalents as used herein refer to molar equivalents, e.g., 1 equivalent of compound I and 1.4 equivalents of diisopropylethylamine, indicating a molar ratio of compound I to diisopropylethylamine of 1: 1.4. the rest is the same.
The "volume amount" of the solvent or solution used in the present invention refers to the weight-to-volume ratio (kg/l) of the starting material (e.g., compound I) or crude product and the solvent, for example, in "compound I (1 equivalent), acetonitrile (8 volume amounts) are added sequentially" in example 1, which means that the weight-to-volume ratio of compound I and the solvent is 1 kg of compound I: 8 liters of solvent. For example, "crude product is recrystallized from 7 volumes of 30% aqueous isopropanol solution" means that the weight to volume ratio of crude product to 30% aqueous isopropanol solution is 1 kg crude product: 7 liters of 30% aqueous isopropanol. The rest is the same.
"weight" of solvent or solution as used herein refers to the weight ratio (kg/kg) of starting material (e.g., compound I) to solvent, e.g., 10 weight of solvent used in example 2, means that the weight ratio of compound I to solvent is 1 kg of compound I: 10 kg of solvent. The rest is the same.
The pharmacopoeia for the people's republic of China described in the present invention is the first part of the pharmacopoeia for the people's republic of China 2010 edition.
Example 1
Figure BDA0002071245520000091
In a 500mL reaction flask, compound I (1 equivalent), acetonitrile (8 volumes), diisopropylethylamine (1.4 equivalents) were added in sequence. And (3) cooling the mixture to-10 to-5 ℃ under stirring, adding sulfuryl fluoride balloons on a reaction bottle, and continuously reacting at-10 to-5 ℃ until the raw materials are not converted any more by HPLC (the consumption of sulfuryl fluoride is about 1.3 equivalent by a balloon weight reduction method). And (3) concentrating the reaction mixture under reduced pressure until the reaction mixture is dried, adding 8 volumes of 25% isopropanol aqueous solution, heating to 80 ℃, stirring for 3 hours, cooling to 5-10 ℃, and performing suction filtration to obtain a florfenicol crude product.
Heating and dissolving the crude product in a 30% isopropanol aqueous solution with the volume of 7 individuals, cooling to 20-25 ℃, cooling to 5-10 ℃, standing and recrystallizing to obtain a florfenicol pure product meeting the national drug dictionary standard, wherein the yield is 85%.
Example 2
Figure BDA0002071245520000092
A1000 ml reaction kettle is prepared, a thermometer is equipped, the compound I (1 equivalent), dichloromethane (10 weight portions) and diisopropylethylamine (1.2 equivalent) are sequentially added at room temperature, the temperature of the mixture is controlled to 15-25 ℃, sulfuryl fluoride gas is slowly introduced, and the pressure is 2-3 atmospheres. Controlling the temperature to be 15-25 ℃, reacting for 24 hours, and then decompressing and concentrating the reaction mixture to recover the solvent. Then adding 8 volumes of 25% isopropanol aqueous solution into the reaction kettle, heating to 80-85 ℃, and stirring for 3 hours. The reaction solution is cooled to 5-10 ℃ and stirred for 1 hour. Suction filtering, washing the filter cake with water, and suction drying. Drying for 16 hours in a vacuum oven at 60-65 ℃ to obtain white solid which meets the drug sales code standard of the people's republic of China and has the yield of 93.0 percent.
Example 3
Figure BDA0002071245520000101
In a 500mL reaction flask, compound I (1 equivalent), acetonitrile (8 volumes), diisopropylethylamine (1.4 equivalents) were added in sequence. Cooling the mixture to-10-5 ℃ while stirring, and introducing sulfuryl fluoride gas. Controlling the aeration speed to keep the internal temperature below-5 ℃. Meanwhile, the pressure of the system is controlled not to exceed 2 atmospheric pressures. The system is controlled to be stirred and reacted at the temperature of minus 10 to minus 5 ℃. And in the reaction, sulfuryl fluoride gas is additionally introduced, and the system pressure is controlled to be maintained at 1-2 atmospheric pressures. The reaction is carried out until the system pressure is not changed any more and the sulfuryl fluoride is not consumed any more, indicating that the reaction is finished. The sulfuryl fluoride was charged in a total amount of 1.5 equivalents. The reaction mixture was then distilled under reduced pressure to remove acetonitrile and solvent-displaced to about 2 volumes of 25% aqueous isopropanol. Adding 8 volumes of 25% isopropanol aqueous solution, stirring at 80 ℃ for 3 hours, cooling to 5-10 ℃, and performing suction filtration to obtain a florfenicol crude product.
Heating and dissolving the crude product in a 30% isopropanol aqueous solution with the volume of 7 individuals, cooling to 20-25 ℃, cooling to 5-10 ℃, standing and recrystallizing to obtain the florfenicol pure product meeting the classical selling standards of the people's republic of China with the yield of 88%.
Example 4
The waste liquid treatment method comprises the following steps: mother liquor obtained after the recrystallization of the florfenicol crude product is firstly concentrated and separated to obtain isopropanol, then sodium hydroxide solid with the weight of 10 percent of the residual liquid is added, and after reflux stirring is carried out for 5 hours, the temperature is reduced. The nuclear magnetic fluorine spectrum detection shows that: at this time, all the acyl fluoride in the waste liquid is converted into fluoride ions.
And after the subsequent treatment by adding equal weight of lime water, filtering and filtering solids, the content of fluorine ions in the obtained waste liquid is reduced to be less than or equal to 10ppm, so that the waste liquid reaches the discharge standard of an industrial park.
After the sodium hydroxide treatment, sodium fluoride can be separated from the treated waste liquid for recycling, and the utilization rate of fluorine atoms is greatly improved.
The florfenicol production method greatly reduces the production cost from the aspects of improving the economic benefit and the market competitiveness. Considering the aspect of reaching the standard of factory environment and safety management, the florfenicol production method abandons the production process with large pollution and large danger, better conforms to the situation that the current regulatory force of environmental protection and safety is unprecedented, and has very important economic significance and social significance.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A method for preparing florfenicol, comprising the steps of:
Figure FDA0002071245510000011
(1) carrying out fluorination reaction on the compound I and a fluorinating agent in an inert solvent in the presence of an organic base to obtain a reaction mixture containing a compound II; the fluorinating reagent is sulfuryl fluoride;
(2) and (3) carrying out ring opening reaction on the reaction mixture containing the compound II obtained in the previous step in an aqueous system to obtain the florfenicol.
2. The method for preparing florfenicol as claimed in claim 1 wherein in step (1), the amount of the fluorinating agent is 1-2.0 times that of compound I.
3. The method for preparing florfenicol as claimed in claim 1 wherein in step (1), the organic base is selected from the group consisting of: triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, or a combination thereof.
4. The method for preparing florfenicol as claimed in claim 1 wherein in step (1), the amount of the organic base is 1-1.5 times that of compound I.
5. The process for producing florfenicol as claimed in claim 1 wherein, in step (1), after the fluorination reaction is completed, the reaction mixture is concentrated, and the concentrated mixture is used in step (2) without separation as a reaction mixture containing compound II.
6. The process for preparing florfenicol of claim 1 wherein, in step (2), the aqueous system is a mixture of a C1-6 alkyl alcohol and water.
7. The method of claim 1, wherein the water content of the aqueous system is 20% to 40%.
8. The method for preparing florfenicol as claimed in claim 1 wherein, in step (2), the temperature of the ring-opening reaction is 60 to 100 ℃.
9. The process for preparing florfenicol as claimed in claim 1 further comprising, after step (2), step (3): and (3) recrystallizing the florfenicol obtained in the step (2) in a water-containing system, filtering after crystallization, and collecting solids to obtain the purified florfenicol.
10. A method for treating a waste liquid, wherein the waste liquid is a waste liquid produced by the production method according to any one of claims 1 to 9; the method comprises the following steps: heating and refluxing the waste liquid and a sodium hydroxide aqueous solution to convert fluorine atoms into fluorine ions; then the waste liquid is treated by lime water, thus forming the waste liquid which reaches the discharge standard of the industrial park.
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