Preparation method of florfenicol

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of florfenicol, which comprises the following steps: by taking (R)-3-amino-4-oxobutyric acid and 4-(methylsulfonyl) phenylboronic acid as raw materials, carrying out asymmetric addition reaction, fluorination reaction and acylation reaction to finally prepare the florfenicol. The preparation method of florfenicol provided by the invention is simple to operate, a target product can be prepared at a high yield (the total yield of three steps is 64-74%), and a key intermediate compound C (ee value gt; 98.2%). # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of florfenicol. Background Art

[0002] Florfenicol, also known as florfen, florfenicolum, etc., is a 3-fluoro derivative of thiamphenicol among chloramphenicol broad-spectrum antibacterial drugs, and is mainly used for the prevention and treatment of animal diseases, the treatment of systemic infections of livestock, poultry and aquatic animals, etc. In recent years, the production and export of florfenicol in China have been increasing continuously, and it has been included in the list of varieties with an annual export amount of more than 100 million US dollars of pharmaceutical raw materials in China, attracting attention.

[0003] The chemical name of florfenicol is 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(methylsulfonyl)phenyl)propan-2-yl)acetamide, and its chemical structural formula is shown as follows: ; At present, there are many literatures reporting the synthesis of florfenicol. For example: CN113874351B, CN111500652B, CN111153838B, CN106278964B, CN102417472B, CN118084814B, CN118084746B, CN113874351B, CN109851534B, etc. However, most of the methods reported above have problems such as long synthesis routes, expensive raw materials, the need to use enzymatic methods, low yields, and low purities.

[0004] In summary, the preparation of florfenicol in the prior art has problems such as long synthesis routes, expensive raw materials, the need to use enzymatic methods, low yields, and low selectivities. Therefore, it is urgent to provide more preparation methods of florfenicol. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method of florfenicol with a short synthesis route, cheap and easily available raw materials, high yield, and high selectivity, so as to solve the problems of long synthesis routes, expensive raw materials, the need to use enzymatic methods, low yields, and low selectivities existing in the prior art.

[0006] The present invention is realized through the following technical solutions. The present invention provides a preparation method of florfenicol, which is characterized by including the following steps: 2) Synthesis of compound C: Compound A, compound B, dichloro-bis(4-methylisopropylphenyl)ruthenium(II), ligand L1 and are sequentially added into a 100 mL round bottom flask, and a mixed solvent of toluene and water is added. Under nitrogen protection, the reaction system is stirred at 80 °C for 12 hours. After the reaction is completed, post-treatment is carried out to obtain compound C; 2) Synthesis of Compound D Under a nitrogen atmosphere, Compound C, silver nitrate, and Selectfluor were successively added to a reaction tube, and then acetone and water were added. The reaction solution was refluxed with stirring for 12 hours. After the reaction was completed, post-treatment was carried out to obtain Compound D; 4) Synthesis of Compound E Compound D was added to methanol. After stirring and dissolving, triethylamine was added, and methyl dichloroacetate was added. The mixture was heated to 50 °C and stirred for reaction for 12 hours. The reaction was monitored by TLC. After the reaction was completed, post-treatment and purification were carried out to obtain Compound E; The specific synthesis route is as follows: 。

[0007] Furthermore, as a preferred technical solution of the present invention, the molar ratio of Compound A, Compound B, ruthenium(II) dichloro bis(4-methylisopropylphenyl), ligand L1, and potassium carbonate in step 1) is: 1:(2 - 3):(0.01 - 0.02):(0.02 - 0.04):(2 - 4); preferably, the molar ratio of Compound A, Compound B, ruthenium(II) dichloro bis(4-methylisopropylphenyl), ligand L1, and potassium carbonate is: 1:(2 - 3):(0.015 - 0.02):(0.03 - 0.04):(2 - 4); more preferably, the molar ratio of Compound A, Compound B, ruthenium(II) dichloro bis(4-methylisopropylphenyl), ligand L1, and potassium carbonate is: 1:2:0.015:0.03:4; Furthermore, as a preferred technical solution of the present invention, the volume ratio of toluene to water in step 1) is 3:1; Furthermore, as a preferred technical solution of the present invention, the structural formula of ligand L1 is: ; Furthermore, as a preferred technical solution of the present invention, the post-treatment steps in step 1) are: after the reaction is completed, it is diluted with water, neutralized with hydrochloric acid, and extracted 3 times with ethyl acetate. After combining the organic phases, it is washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent is concentrated under reduced pressure to obtain a residue, which is then purified by silica gel column chromatography. The eluent is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 10:1.

[0008] Further, as a preferred technical solution of the present invention, the molar ratio of compound C, silver nitrate and Selectfluor in step 2) is: 1:(0.1 - 0.5):(1 - 5); preferably, the molar ratio of compound C, silver nitrate and Selectfluor in step 2) is: 1:(0.2 - 0.3):(2 - 3); more preferably, the molar ratio of compound C, silver nitrate and Selectfluor in step 2) is: 1:0.2:2; Further, as a preferred technical solution of the present invention, the volume ratio of acetone to water in step 2) is: 1:1; Further, as a preferred technical solution of the present invention, the post-treatment steps in step 2) are: cooling the system to room temperature, then extracting 3 times with dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying the crude product by silica gel column chromatography, and the eluent is n-hexane; Further, as a preferred technical solution of the present invention, the CAS number of Selectfluor in step 2) is: 414 - 380 - 4, and the structural formula of Selectfluor is: ; Further, as a preferred technical solution of the present invention, the molar ratio of compound D, triethylamine and methyl dichloroacetate in step 3) is: 1:(1 - 3):(1 - 3); preferably, the molar ratio of compound D, triethylamine and methyl dichloroacetate in step 3) is: 1:(2 - 3):(2.5 - 3); more preferably, the molar ratio of compound D, triethylamine and methyl dichloroacetate in step 3) is: 1:3:2.5; Further, as a preferred technical solution of the present invention, the post-treatment steps in step 3) are: after the reaction is completed, rotary evaporating to remove methanol, adding water, adding dichloromethane for extraction, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, removing the solvent under reduced pressure, and purifying the residue by column chromatography, and the eluent is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2:1.

[0009] Beneficial effects: The preparation method of florfenicol provided by the present invention uses (R)-3-amino-4-oxobutyric acid and 4-(methylsulfonyl)phenylboronic acid as raw materials, and finally prepares florfenicol through an asymmetric addition reaction, a fluorination reaction and an acylation reaction. The preparation method of florfenicol provided by the present invention is not only simple in operation, but also can prepare the target product with a high yield (the total yield of three steps is 64 - 74%), and can prepare the key intermediate compound C with high selectivity (ee value > 98.2%). Description of the drawings

[0010] 1) Figure 11H NMR spectrum of florfenicol prepared in Example 1 1 H NMR spectrum Detailed implementation mode

[0011] The present invention will be further described in detail below in conjunction with examples, but the content of the invention is not limited to the examples.

[0012] Example 1 Preparation of florfenicol

[0013] The specific synthesis steps are as follows: 1) Synthesis of compound C: Compound A (1.17 g, 10 mmol), compound B (4.0 g, 20 mmol), dichloro bis(4-methylcumyl)ruthenium(II) (0.092 g, 0.15 mmol), ligand L1 (0.14 g, 0.3 mmol) and (5.53 g, 40 mmol) were successively added into a 150 mL round bottom flask, and a mixed solvent of toluene (60 mL) and water (20 mL) was added. Under nitrogen protection, the reaction system was stirred at 80 °C for 12 hours. After the reaction was completed, it was diluted with 40 mL of water, neutralized with hydrochloric acid, and extracted with ethyl acetate (60 mL × 3 times). After combining the organic phases, they were washed with saturated brine (60 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain 2.51 g of compound C with a yield of 92% and an ee value of 99.0% for compound C. The ee value was determined by a chiral chromatographic column OD-H column.

[0014] 2) Synthesis of compound D Under a nitrogen atmosphere, compound C (1.37 g, 5 mmol), silver nitrate (0.17 g, 1 mmol) and Selectfluor (3.54 g, 10 mmol) were successively added to a reaction tube, and then 30 mL each of acetone and water were added. The reaction solution was refluxed with stirring for 12 hours. The system was cooled to room temperature, and then extracted with dichloromethane (50 mL × 3). After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography with n-hexane as the eluent to obtain 1.09 g of compound D with a yield of 88%.

[0015] 3) Synthesis of compound E Compound D (0.124 g, 0.5 mmol) was added to 5 mL of methanol. After stirring to dissolve, triethylamine (0.15 g, 1.5 mmol) was added, followed by methyl dichloroacetate (0.18 g, 1.25 mmol). The mixture was heated to 50 °C and stirred for 12 hours. The reaction was monitored by TLC. After the reaction was completed, methanol was removed by rotary evaporation. 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to obtain 0.163 g of compound E with a yield of 91%. 1 1H NMR (DMSO-d6, 400 M): δ 8.61 (d, 1H), 7.83 (d, 2H), 7.59 (d, 2H), 6.45 (s, 1H), 6.13 (d, 1H), 4.96 - 4.94 (m, 1H), 4.71 - 4.60 (m, 1H), 4.58 - 4.24 (m, 2H), 3.13 (s, 3H). Example 2 Preparation of Florfenicol

[0016] The specific synthesis steps are as follows: 1) Synthesis of compound C: Compound A (1.17 g, 10 mmol), compound B (4.0 g, 20 mmol), dichloro-bis(4-methylisopropylphenyl)ruthenium(II) (0.061 g, 0.1 mmol), ligand L1 (0.091 g, 0.2 mmol) and (2.76 g, 20 mmol) were successively added to a 150 mL round-bottom flask, and a mixed solvent of toluene (60 mL) and water (20 mL) was added. Under nitrogen protection, the reaction system was stirred at 80 °C for 12 hours. After the reaction was completed, it was diluted with 40 mL of water, neutralized with hydrochloric acid, and extracted with ethyl acetate (60 mL × 3 times). The combined organic phases were washed with saturated brine (60 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain a residue, which was further purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain 2.32 g of crude compound C with a yield of 85% and an ee value of 98.2%. The ee value was determined by a chiral chromatographic column OD-H column.

[0017] 2) Synthesis of compound D Under a nitrogen atmosphere, compound C (1.37 g, 5 mmol), silver nitrate (0.17 g, 1 mmol), and Selectfluor (3.54 g, 10 mmol) were successively added to a reaction tube. Then, 30 mL each of acetone and water were added. The reaction solution was refluxed with stirring for 12 hours. The system was cooled to room temperature, and then extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography with n-hexane as the eluent to obtain 1.04 g of compound D with a yield of 84%.

[0018] 3) Synthesis of compound E Compound D (0.124 g, 0.5 mmol) was added to 5 mL of methanol and stirred until dissolved. Then, triethylamine (0.15 g, 1.5 mmol) was added, followed by methyl dichloroacetate (0.18 g, 1.25 mmol). The mixture was heated to 50 °C and stirred for 12 hours. The reaction was monitored by TLC. After completion of the reaction, methanol was removed by rotary evaporation. 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to obtain 0.161 g of compound E with a yield of 90%.

[0019] Comparative Example 1: Preparation of florfenicol

[0020] The specific synthesis steps are as follows: 1) Synthesis of compound C: Compound A (1.17 g, 10 mmol), compound B (4.0 g, 20 mmol), dichloro-bis(4-methylcumyl)ruthenium(II) (0.061 g, 0.1 mmol), ligand L2 (0.066 g, 0.2 mmol), and (2.76 g, 20 mmol) were successively added to a 150 mL round-bottom flask, and a mixed solvent of toluene (60 mL) and water (20 mL) was added. Under nitrogen protection, the reaction system was stirred at 80 °C for 12 hours. After completion of the reaction, it was diluted with 40 mL of water, neutralized with hydrochloric acid, and extracted with ethyl acetate (60 mL × 3 times). The combined organic phases were washed with saturated brine (at 60 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain a residue, which was further purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain 2.13 g of compound C with a yield of 78% and an ee value of 90.4%. The ee value was determined by a chiral chromatographic column OD-H column.

[0021] 2) Synthesis of Compound D Under a nitrogen atmosphere, compound C (1.37 g, 5 mmol), silver nitrate (0.17 g, 1 mmol), and Selectfluor (3.54 g, 10 mmol) were successively added to a reaction tube. Then, 30 mL each of acetone and water were added. The reaction solution was refluxed with stirring for 12 hours. The system was cooled to room temperature, and then extracted with dichloromethane (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography with n-hexane as the eluent to obtain 1.0 g of compound D with a yield of 81%.

[0022] 3) Synthesis of Compound E Compound D (0.124 g, 0.5 mmol) was added to 5 mL of methanol. After stirring to dissolve, triethylamine (0.15 g, 1.5 mmol) was added, followed by methyl dichloroacetate (0.18 g, 1.25 mmol). The mixture was heated to 50 °C and stirred for 12 hours. The reaction was monitored by TLC. After completion of the reaction, methanol was removed by rotary evaporation. 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to obtain 0.157 g of compound E with a yield of 88%.

[0023] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. For those of ordinary skill in the art, modifications or variations can be made according to the above description. All such modifications and variations should fall within the protection scope of the appended claims of the present invention.

Claims

1. A preparation method of florfenicol, characterized in that, It includes the following steps: 1) Synthesis of compound C: Compound A, Compound B, dichloro-bis(4-methylcumyl)ruthenium(II), ligand L1 and were successively added into a 100 mL round-bottom flask, and a mixed solvent of toluene and water was added. Under nitrogen protection, the reaction system was stirred at 80 °C for 12 hours. After the reaction was completed, compound C was obtained by post-treatment; 2) Synthesis of compound D Under a nitrogen atmosphere, compound C, silver nitrate and Selectfluor are successively added into a reaction tube, then acetone and water are added, and the reaction solution is refluxed with stirring for 12 hours. After the reaction is completed, compound D is obtained through post-treatment; 3) Synthesis of compound E Compound D is added into methanol, stirred and dissolved, then triethylamine is added, methyl dichloroacetate is added, and the mixture is heated to 50 °C and stirred for reaction for 12 hours. The reaction is monitored by TLC. After the reaction is completed, compound E is obtained through post-treatment and purification; The specific synthesis route is as follows: ； The structural formula of ligand L1 in step 1) is as follows: ; The structural formula of Selectfluor in step 2) is as follows: .

2. The preparation method of florfenicol according to claim 1, wherein In step 1), the molar ratio of compound A, compound B, dichloro-bis(4-methylisopropylphenyl)ruthenium(II), ligand L1 and potassium carbonate is: 1:(2 - 3):(0.01 - 0.02):(0.02 - 0.04):(2 - 4); preferably, the molar ratio of compound A, compound B, dichloro-bis(4-methylisopropylphenyl)ruthenium(II), ligand L1 and potassium carbonate is: 1:(2 - 3):(0.015 - 0.02):(0.03 - 0.04):(2 - 4); In step 1), the volume ratio of toluene to water is 3:

1.

3. The preparation method of florfenicol according to claim 2, characterized in that, In step 1), the molar ratio of compound A, compound B, dichloro-bis(4-methylisopropylphenyl)ruthenium(II), ligand L1 and potassium carbonate is: 1:2:0.015:0.03:

4.

4. The preparation method of florfenicol according to claim 1, characterized in that, The post-treatment steps in step 1) are: after the reaction is completed, it is diluted with water, neutralized with hydrochloric acid, and extracted 3 times with ethyl acetate. After combining the organic phases, it is washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to obtain a residue, and then purified by silica gel column chromatography. The eluent is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 10:

1.

5. The preparation method of florfenicol according to claim 1, characterized in that, In step 2), the molar ratio of compound C, silver nitrate and Selectfluor is: 1:(0.1 - 0.5):(1 - 5); preferably, in step 2), the molar ratio of compound C, silver nitrate and Selectfluor is: 1:(0.2 - 0.3):(2 - 3); Further, as a preferred technical solution of the present invention, the volume ratio of acetone to water in step 2) is: 1:

1.

6. The preparation method of florfenicol according to claim 5, characterized in that, In step 2), the molar ratio of compound C, silver nitrate and Selectfluor is: 1:0.2:

2.

7. The preparation method of florfenicol according to claim 1, characterized in that, The post-treatment steps in step 2) are: the system is cooled to room temperature, then extracted 3 times with dichloromethane, the organic phases are combined and dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated, and the crude product is purified by silica gel column chromatography. The eluent is n-hexane.

8. The preparation method of florfenicol according to claim 1, characterized in that, In step 3), the molar ratio of compound D, triethylamine and methyl dichloroacetate is: 1:(1 - 3):(1 - 3); preferably, in step 3), the molar ratio of compound D, triethylamine and methyl dichloroacetate is: 1:(2 - 3):(2.5 - 3).

9. The preparation method of florfenicol according to claim 8, characterized in that, In step 3), the molar ratio of compound D, triethylamine and methyl dichloroacetate is: 1:3:2.

5.

10. The preparation method of florfenicol according to claim 1, characterized in that, The post-treatment steps in step 3) are as follows: after the reaction is completed, rotary evaporation is used to remove methanol, water is added, dichloromethane is added for extraction, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent is removed under reduced pressure, and the residue is purified by column chromatography. The eluent is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 2:1.

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