WO2020238779A1

WO2020238779A1 - Method for synthesizing florfenicol

Info

Publication number: WO2020238779A1
Application number: PCT/CN2020/091701
Authority: WO
Inventors: 朱文峰; 郭朋; 黄嘉慧
Original assignee: 上海博璞诺科技发展有限公司
Priority date: 2019-05-24
Filing date: 2020-05-22
Publication date: 2020-12-03
Also published as: CN113874351B; CN113874351A; CN111978218A

Abstract

The present invention relates to a method for synthesizing florfenicol. The method comprises the steps of: using sulfuryl fluoride as a fluorinating reagent to fluorinate compound I to obtain a product, and then performing a ring opening reaction in an aqueous system, so that florfenicol can be easily prepared. The present method is simple to operate, produces few by-products, is safe and environmentally friendly, has low production cost, and is suitable for industrial use.

Description

A kind of synthetic method of florfenicol

Technical field

The invention belongs to the field of drug synthesis, and specifically relates to a method for synthesizing florfenicol.

Background technique

Florfenicol (Florfenicol), also known as fluprofen, florfenicol, etc., is the 3-position fluorine derivative of thiamphenicol in chloramphenicol broad-spectrum antibacterial drugs. It is mainly used for the prevention and treatment of animal diseases and livestock Treatment of systemic infections in poultry and aquatic animals, etc. In recent years, the production and export of florfenicol in my country have been increasing, and it has been listed in the list of my country's pharmaceutical raw materials with an annual export value of more than 100 million US dollars, attracting attention.

The chemical name of Florfenicol is 2,2-Dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(methylsulfonyl)phenyl)propan-2- Yl)acetamide, its chemical structure is shown in the following formula:

At present, the production process of florfenicol from various domestic manufacturers is relatively consistent. All of them use D-p-methylsulfonyl phenylserine ethyl ester as raw material, through reduction, cyclization, fluorination, and hydrolysis to obtain florfenicol raw materials.

Among them, the fluorination step adopts the Ishikawa reagent fluorination method for fluorination. The fluorinated reagent accounts for about 15% of the total material cost. The actual amount of the process is 1.5 times the theoretical amount of the chemical reaction, and the theoretical utilization rate of the fluorine atom is only one-sixth, causing a large amount of fluorine-containing materials to become waste. Moreover, Ishikawa reagent (N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine) is converted into by-product N,N-diethyl-2,3, 3,3-Tetrafluoropropionamide and fluoride ion. Among them, N,N-diethyl-2,3,3,3-tetrafluoropropionamide is difficult to recycle, and its fluorine-containing wastewater cannot meet the discharge standard. The poisoning effect of the treatment system is very serious. In addition, due to the stability of Ishikawa reagent, factory production usually adopts off-the-shelf methods. The production process of this reagent requires ultra-low temperature, high pressure, high temperature and other conditions, which increases energy consumption and safety risks.

With the increasing demand for florfenicol in the market, the development of a new synthetic process method for florfenicol to reduce the cost of the existing production process, avoiding severely polluting process routes and potentially dangerous reactions is of great economic importance Meaning and social significance.

Summary of the invention

Aiming at the deficiencies and defects in the prior art, the purpose of the present invention is to provide a simpler, more environmentally friendly and economical synthesis method of florfenicol suitable for industrialization.

In order to achieve the above objectives, the present invention provides the following technical solutions:

The first aspect of the present invention provides a method for preparing florfenicol, the method comprising the steps:

(1) In an inert solvent, in the presence of an organic base, the compound I is subjected to a fluorination reaction with a fluorinating reagent to obtain a reaction mixture containing compound II; the fluorinating reagent is sulfuryl fluoride;

(2) In an aqueous system, the reaction mixture containing compound II obtained in the foregoing step is subjected to a ring-opening reaction to obtain florfenicol.

In another preferred embodiment, in step (1), the inert solvent is selected from the following group: acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran or a combination thereof.

In another preferred example, in step (1), the amount ratio of compound I to the inert solvent is 1 kg: 5-15 kg or liter; preferably 1 kg: 7-10 kg or liter.

In another preferred example, in step (1), the amount of the fluorinating reagent is 1 to 2.0 times that of compound I.

In another preferred embodiment, the amount of the fluorinating reagent is 1 to 1.5 times that of compound I.

In another preferred example, 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 step (1), the amount of the organic base is 1 to 1.5 times that of compound I.

In another preferred example, in step (1), the amount of the organic base is 1.2 to 1.5 times that of compound I.

In another preferred example, in step (1), the temperature of the fluorination reaction is -15 to 30 degrees; preferably -15 to 0 degrees.

In another preferred example, in step (1), when the fluorination reaction is carried out, the system pressure is 1 to 3 atmospheres or 1 to 2 atmospheres or 2 to 3 atmospheres.

In another preferred example, in step (1), the fluorination reaction time is 1 hour to 24 hours.

In another preferred example, in step (1), after the fluorination reaction is completed, the reaction mixture is concentrated, and the concentrated mixture is a reaction mixture containing compound II, which is directly used in step (2) without separation.

In another preferred example, in step (2), the aqueous system is a mixture of C1-6 alkyl alcohol and water.

In another preferred embodiment, the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.

In another preferred example, the volume dosage (liter) of the aqueous system is 5-10 times the weight dosage (kg) of Compound I; preferably 7-8 times.

In another preferred example, the water content in the water-containing system is 20%-40%.

In another preferred example, the water content in the water-containing system is 20%-30%; more preferably, the water content is 25%-30%.

In another preferred example, in step (2), the temperature of the ring-opening reaction is 60-100 degrees.

In another preferred embodiment, the temperature of the ring-opening reaction is 80-85 degrees.

In another preferred example, in step (2), the time of the ring-opening reaction is 1 hour to 10 hours; preferably 2 to 4 hours.

In another preferred example, in step (2), after the ring-opening reaction is completed, the reaction mixture is filtered to collect the solid as florfenicol.

In another preferred example, in step (2), after the completion of the ring-opening reaction and before the filtration, the method further includes cooling the reaction mixture after the completion of the reaction (for example, cooling to 0-10 degrees).

In another preferred example, after step (2), it further includes step (3): recrystallize the florfenicol obtained in step (2) in an aqueous system, filter after crystallization, and collect the solids to obtain purification Florfenicol.

In another preferred embodiment, the aqueous system is a mixture of C1-6 alkyl alcohol and water.

In another preferred embodiment, the C1-6 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol or tert-butanol.

In another preferred example, the water content in the aqueous system is 20%-40%; preferably 25%-30%.

In another preferred embodiment, the recrystallization includes the steps of: first dissolving the florfenicol obtained in step (2), and then cooling and standing for crystallization.

In another preferred embodiment, the cooling includes: first cooling to 20-25°C; then cooling to 5-10°C.

In another preferred example, the purified florfenicol obtained in step (3) meets the standards of the Pharmacopoeia sold in the People's Republic of China.

In another preferred example, after step (2) and/or step (3), the waste liquid treatment step (4) is further included: the waste liquid obtained by the preparation method and the sodium hydroxide aqueous solution are heated and refluxed, and the The fluorine atoms in the waste liquid are converted into fluorine ions.

In another preferred example, the sodium hydroxide aqueous solution is a 5%-20% sodium hydroxide aqueous solution by weight; preferably 5%-15% sodium hydroxide aqueous solution.

In another preferred embodiment, 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 example, the heating and refluxing treatment is 1-10 hours; preferably 1-8 hours; more preferably 3-6 hours.

In another preferred example, step (5) is included after step (4); the waste liquid processed in step (4) is treated with lime water, and after filtration, the filtrate reaches the discharge standard of the industrial park.

In another preferred embodiment, the weight of the lime water is equivalent to the weight of the waste liquid obtained in the previous step.

In another preferred example, the said meeting the emission standard of the industrial park means that the content of fluoride ion in the filtrate is ≤ 10 ppm.

In another preferred example, the waste liquid obtained by the preparation method in step (4) is the filtrate obtained in step (2) and/or step (3).

The second aspect of the present invention provides a method for processing waste liquid, the waste liquid is the waste liquid produced by the preparation method described in the first aspect; the method includes the step of heating the waste liquid and the sodium hydroxide aqueous solution Reflux treatment converts fluorine atoms into fluoride ions; then after lime water treatment, a waste liquid meeting the discharge standards of the industrial park is formed.

In another preferred embodiment, the fluoride ion content in the waste liquid that meets the discharge standard of the industrial park is less than or equal to 10 ppm.

Compared with the existing method, the synthesis method of the present invention has the advantages of simple operation, fewer by-products, safety and environmental protection, and low production cost, and is suitable for industrial production.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.

Detailed ways

After long-term and in-depth research, the inventor unexpectedly discovered a production method of florfenicol that is very suitable for industrialization. The method uses sulfuryl fluoride as a fluorination reagent to fluorinate compound I. After the reaction, the fluorine The chemical product can be put into the ring-opening reaction without additional purification and separation, thereby obtaining florfenicol. In particular, the post-treatment of the waste liquid generated by the production method is very simple, and only sodium hydroxide and lime water are used successively, and the waste liquid can meet the industrial discharge standard. Moreover, the fluorinated reagent has a stable source and low cost, which can greatly reduce the cost of the fluorination reaction. Correspondingly, the synthesis cost of florfenicol is also greatly reduced, which is very suitable for industrialization. On this basis, the inventor completed the present invention.

The present invention provides a method for preparing florfenicol, the method comprising the steps:

(a) In an inert solvent, in the presence of an organic base, the compound I is subjected to a fluorination reaction with sulfuryl fluoride. After the fluorination reaction is completed, the reaction mixture is concentrated, and the concentrate is collected. The concentrate does not undergo any separation. The purification step is directly used in the next step;

(b) In an aqueous system, subjecting the concentrate obtained in the previous step to a ring-opening reaction to obtain florfenicol.

In another preferred example, in step (a), the amount ratio of compound I to the inert solvent is 1 kg: 5-15 kg or liter; preferably 1 kg: 7-10 kg or liter.

In another preferred embodiment, in step (a), the inert solvent is selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran or a combination thereof.

In another preferred example, in step (a), the amount of the fluorinating reagent is 1 to 2.0 times that of compound I; preferably 1 to 1.5 times.

In another preferred embodiment, in step (a), the organic base is selected from the following group: triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or a combination thereof.

In another preferred example, in step (a), the amount of the organic base is 1 to 1.5 times that of Compound I; preferably 1.2 to 1.5 times.

In another preferred example, in step (a), the temperature of the fluorination reaction is -15 to 30 degrees; preferably -15 to 0 degrees.

In another preferred example, in step (a), when the fluorination reaction is carried out, the system pressure is 1 to 3 atmospheres or 1 to 2 atmospheres or 2 to 3 atmospheres.

In another preferred example, in step (a), the fluorination reaction time is 1 hour 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 water content in the water-containing system is 20%-40%; more preferably, the water content is 25%-30%.

In another preferred example, in step (b), the temperature of the ring-opening reaction is 60-100 degrees; preferably 80-85 degrees.

In another preferred example, in step (b), the ring-opening reaction time is 1 hour to 10 hours; preferably 2 to 4 hours.

In another preferred example, in step (b), after the ring-opening reaction is completed, the reaction mixture is filtered to collect the solid as florfenicol.

In another preferred example, in step (b), after the completion of the ring-opening reaction and before the filtration, it further includes cooling the reaction mixture after the completion of the reaction (for example, cooling to 0-10 degrees).

In another preferred example, after step (b), it further includes step (c): recrystallize the florfenicol obtained in step (b) in an aqueous system, filter after crystallization, and collect the solid to obtain a purified Florfenicol.

In another preferred embodiment, the purified florfenicol obtained in step (c) meets the standards of the Pharmacopoeia of the People's Republic of China.

The invention also provides a waste liquid treatment method.

The treatment method of the waste liquid includes a sodium hydroxide treatment step: the waste liquid and the sodium hydroxide aqueous solution are heated and refluxed, so that all the fluorine atoms in the waste liquid are converted into fluorine ions.

After sodium hydroxide treatment, all the fluorine atoms in the waste liquid are converted into sodium fluoride fluoride ions, which form sodium fluoride with sodium ions. The sodium fluoride can be recycled.

The waste liquid treatment method further includes a lime water treatment step: the sodium hydroxide treated waste liquid obtained in the above steps is treated with lime water and filtered to form a waste liquid meeting the discharge standard of the industrial park.

The waste liquid may be the filtrate obtained in step (b) and/or step (c).

The waste liquid of the present invention contains the compound salt of fluorosulfonic acid and organic base and excess sulfuryl fluoride.

The main advantages of the present invention are:

In the preparation method of the present invention, sulfuryl fluoride is used as a fluorination reagent, no additional fluorine source is needed, and the utilization rate of fluorine atoms is high, and the utilization rate can reach 50%. The fluorinated reagent is a widely used fumigant sulfuryl fluoride, with stable source and low cost, and the amount of the fluorinated reagent is small, so the cost of the fluorinated reagent is reduced by more than 50%.

In the preparation method of the present invention, the reaction of each step does not require harsh operations such as ultra-low temperature, high temperature, high pressure, etc., and no complicated post-treatment between steps. This method is safer, more economical and simpler.

The reaction yield of the preparation method of the invention is high and the product quality meets the standard.

More importantly, in the preparation method of the present invention, the by-product is single, and all the fluorine atoms in the waste liquid can be converted into recoverable fluoride ions after simple treatment. Moreover, the waste liquid can meet the discharge standards of the industrial park after simple treatment. Therefore, this method is more environmentally friendly.

In summary, the method of the present invention is very suitable as an industrial production method for florfenicol.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

The equivalent used in the present invention refers to a molar equivalent. For example, compound I is 1 equivalent and diisopropylethylamine is 1.4 equivalents, which means that the molar ratio of compound I and diisopropylethylamine is 1:1.4. The rest is similar.

The "volume" of the solvent or solution used in the present invention refers to the weight-volume ratio of the raw material (such as compound I) or the crude product and the solvent (kg/liter), for example, in Example 1, "add compound I (1 equivalent), Acetonitrile (8 volumes)” means that the weight-volume ratio of compound I to solvent is 1 kg compound I: 8 liters of solvent. For example, "the crude product is recrystallized in 7 volumes of 30% isopropanol aqueous solution", it means that the weight-volume ratio of the crude product to the 30% isopropanol aqueous solution is 1 kg crude product: 7 liters of 30% isopropanol aqueous solution. The rest is similar.

The "weight" of the solvent or solution used in the present invention refers to the weight-to-weight ratio of the raw material (such as compound I) and the solvent (kg/kg). For example, if 10 weights of the solvent are used in Example 2, it means the weight of the compound I and the solvent The weight-to-weight ratio is 1 kg of compound I: 10 kg of solvent. The rest is similar.

The Pharmacopoeia of the People's Republic of China in the present invention is the first part of the 2010 edition of the Pharmacopoeia of the People's Republic of China.

Example 1

In a 500 mL reaction flask, compound I (1 equivalent), acetonitrile (8 volumes), and diisopropylethylamine (1.4 equivalents) were sequentially added. After the above mixture was stirred and cooled to -10～-5 degrees Celsius, a sulfuryl fluoride balloon was added to the reaction flask, and the reaction was continued at a temperature of -10～-5 degrees Celsius until the raw materials were no longer converted by HPLC (balloon weight reduction method calculated sulfuryl Fluorine consumption is about 1.3 equivalents). After the reaction mixture was concentrated to dryness under reduced pressure, 8 volumes of 25% isopropanol aqueous solution were added, the temperature was raised to 80 degrees Celsius and stirred for 3 hours, then the temperature was reduced to 5-10 degrees, and the crude florfenicol was obtained by suction filtration.

The crude product is heated and dissolved in 7 volumes of 30% isopropanol aqueous solution, and then the temperature is first cooled to 20-25°C, and then cooled to 5-10°C. After standing and recrystallizing, fluorobenzene meeting the standards of the People’s Republic of China Pharmacopoeia is obtained. Nicol is pure product with a yield of 85%.

Example 2

Prepare a 1000ml reactor with a thermometer. Add compound I (1 equivalent), dichloromethane (10 weights), and diisopropylethylamine (1.2 equivalents) at room temperature. The temperature of the above mixture is controlled to 15 ~25 degrees Celsius, slowly pass in sulfuryl fluoride gas at a pressure of 2-3 atmospheres. The temperature was controlled at 15-25 degrees Celsius and reacted for 24 hours, and then the reaction mixture was concentrated under reduced pressure to recover the solvent. Then, 8 volumes of 25% isopropanol aqueous solution were added to the reaction kettle, the temperature was raised to 80-85 degrees Celsius, and the mixture was stirred for 3 hours. The reaction solution was cooled to 5-10 degrees Celsius and stirred for 1 hour. Suction filtration, the filter cake is washed with water and drained. It was dried in a vacuum oven at 60-65 degrees Celsius for 16 hours to obtain a white solid, which met the standards of the Pharmacopoeia of the People’s Republic of China, with a yield of 93.0%.

Example 3

In a 500 mL reaction flask, compound I (1 equivalent), acetonitrile (8 volumes), and diisopropylethylamine (1.4 equivalents) were sequentially added. After the above mixture is stirred and cooled to -10 to -5 degrees Celsius, sulfuryl fluoride gas is introduced. Control the ventilation speed to keep the internal temperature below -5 degrees Celsius. At the same time, control the system pressure not to exceed 2 atmospheres. The system is controlled to stir and react at -10 to -5 degrees Celsius. During the reaction, sulfuryl fluoride gas was added to control the pressure of the system to maintain 1 to 2 atmospheres. After the reaction, the system pressure no longer changes and the sulfuryl fluoride is no longer consumed, indicating the end of the reaction. A total of 1.5 equivalents of sulfuryl fluoride was injected. Then the reaction mixture was distilled under reduced pressure to remove acetonitrile, and the solvent was replaced with about 2 volumes of 25% isopropanol aqueous solution. Add 8 volumes of 25% isopropanol aqueous solution to the system, stir at 80 degrees Celsius for 3 hours, then cool to 5-10 degrees Celsius, and filter with suction to obtain crude florfenicol.

The crude product is heated and dissolved in 7 volumes of 30% isopropanol aqueous solution, and then the temperature is first cooled to 20-25°C, and then cooled to 5-10°C. After standing and recrystallizing, fluorobenzene meeting the standards of the People’s Republic of China Pharmacopoeia is obtained. Nicol is pure product with a yield of 88%.

Example 4

Waste liquid treatment method: the mother liquor after the crude florfenicol is recrystallized, the isopropanol is separated by concentration first, sodium hydroxide solid of 10% by weight of the remaining liquid is added, and the temperature is cooled after refluxing and stirring for 5 hours. The nuclear magnetic fluorine spectrum test showed that all the acid fluoride in the waste liquid was converted into fluoride ion at this time.

Subsequent addition of equal weight of lime water for treatment, filtration, and filtration of solids, the fluoride ion content in the waste liquid obtained is reduced to ≤10ppm, which meets the discharge standard of the industrial park.

After sodium hydroxide treatment, sodium fluoride can also be separated from the treated waste liquid and recycled, which greatly improves the utilization rate of fluorine atoms.

From the perspective of improving economic efficiency and improving market competitiveness, the production method of florfenicol of the present invention greatly reduces the production cost. Considering the compliance of factory environment and safety management standards, the florfenicol production method of the present invention discards the pollution and dangerous production process, and is more in line with the unprecedented situation of current environmental protection and safety compliance supervision. Important economic and social significance.

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A preparation method of florfenicol, characterized in that the method comprises the steps:

(1) In an inert solvent, in the presence of an organic base, the compound I is subjected to a fluorination reaction with a fluorinating reagent to obtain a reaction mixture containing compound II; the fluorinating reagent is sulfuryl fluoride;

(2) In an aqueous system, the reaction mixture containing compound II obtained in the foregoing step is subjected to a ring-opening reaction to obtain florfenicol.
The method for preparing florfenicol according to claim 1, wherein in step (1), the amount of the fluorinating reagent is 1 to 2.0 times that of compound I.
The method for preparing florfenicol according to claim 1, wherein in step (1), the organic base is selected from the following group: triethylamine, diisopropylethylamine, 4-dimethylamino Pyridine or a combination thereof.
The method for preparing florfenicol according to claim 1, wherein in step (1), the amount of the organic base is 1 to 1.5 times that of compound I.
The preparation method of florfenicol according to claim 1, wherein in step (1), after the fluorination reaction is completed, the reaction mixture is concentrated, and the concentrated mixture is a reaction mixture containing compound II , Directly used in step (2) without separation.
The method for preparing florfenicol according to claim 1, wherein in step (2), the aqueous system is a mixture of C1-6 alkyl alcohol and water.
The method for preparing florfenicol according to claim 1, wherein the water content in the aqueous system is 20%-40%.
The method for preparing florfenicol according to claim 1, wherein in step (2), the temperature of the ring-opening reaction is 60-100 degrees.
The preparation method of florfenicol according to claim 1, characterized in that, after step (2), it further comprises step (3): recrystallizing the florfenicol obtained in step (2) in an aqueous system After crystallization, filter and collect the solid to obtain purified florfenicol.
A method for processing waste liquid, characterized in that the waste liquid is the waste liquid produced by the preparation method of any one of claims 1-9; the method includes the step of: combining the waste liquid with sodium hydroxide The aqueous solution is heated and refluxed to convert the fluorine atoms into fluorine ions; then, after being treated with lime water, it forms a waste liquid that meets the discharge standards of the industrial park.