A preparation method of florfenicol intermediate

Abstract

The present invention relates to a method for preparing a florfenicol intermediate, and belongs to the technical field of drug synthesis. The present invention performs a reduction reaction on compound I ((2R, 3S)-2-amino-3-hydroxy-3-(4-(methylsulfonyl)phenyl)ethyl propionate) under the action of a reducing agent to obtain compound II ((1R, 2S)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol); and then prepares compound III ((4R, 5R)-2-(1,1-dichloromethyl)-4-hydroxymethyl-5-(4-methylsulfonylphenyl)-4,5-oxazoline) through a cyclization reaction. The starting raw materials for the preparation method of the florfenicol intermediate provided by the present invention are simple and easy to obtain, and the product can be obtained only by the steps of reduction and cyclization. At the same time, after carrying out multiple batches of amplification tests, the yield and purity of the product remain stable, which is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a florfenicol intermediate. Background Art

[0002] Florfenicol, also known as fluorosulfamethoxazole, is a commonly used veterinary antibiotic with a broad antibacterial spectrum, strong antibacterial effect, and low minimum inhibitory concentration (MIC). The antibacterial effect is 15-20 times that of chloramphenicol and thiamphenicol. The drug concentration in the tissue can reach the peak 60 minutes after administration of feed, which can quickly control the disease. It has the characteristics of high safety, non-toxicity, and no residue. It has no potential risk of causing aplastic anemia and is suitable for large-scale farms. It is mainly used to treat bovine respiratory diseases caused by Pasteurella and Haemophilus. It has a good effect on bovine foot rot caused by Fusobacterium. It is also used for infectious diseases of pigs and chickens caused by sensitive bacteria and bacterial diseases of fish.

[0003] There are many synthetic process routes for florfenicol. The main synthetic method is to use D-p-methylsulfonylphenylserine ethyl ester (CAS: 36983-12-7) as raw material, reduce it with potassium borohydride, and cyclize it with dichloroacetonitrile to obtain the cyclocompound oxazoline, also known as (4R,5R)-2-(1,1-dichloromethyl)-4-hydroxymethyl-5-(4-methylsulfonylphenyl)-4,5-oxazoline; finally, the cyclocompound oxazoline is fluorinated with Ishikawa reagent and then hydrolyzed to obtain florfenicol. The above-mentioned synthetic method is disclosed in US Patent No. 5,382,673, but the preparation process is relatively complicated. First, the preparation of Ishikawa reagent requires that dichloromethane and diethylamine be added evenly in the reactor, and then hexafluoropropylene is slowly introduced below 10°C, and stirred at room temperature for 18 hours to obtain Ishikawa reagent. Secondly, the cyclocompound oxazoline and the Ishikawa reagent need to be fluorinated at about 100°C for 2 hours to recover the solvent; the product is added to a sodium acetate and isopropanol aqueous solution and refluxed for 4 hours, and the solvent is recovered after hydrolysis, concentrated, crystallized, centrifuged, and refined to obtain the finished product. Although the yield of this process can reach 82.1%, the complex preparation process limits industrial production. Summary of the invention

[0004] In view of the problem that the preparation process of a florfenicol intermediate in the prior art is complicated, the present invention provides a method for preparing a florfenicol intermediate, taking (2R, 3S)-2-amino-3-hydroxy-3-(4-(methylsulfonyl)phenyl)propionic acid ethyl ester as a starting material, and preparing the florfenicol intermediate through reduction and cyclization reactions.

[0005] The technical solution of the present invention is as follows:

[0006] A method for preparing a florfenicol intermediate, the reaction formula is as follows:

[0007] ;

[0008] Compound Ⅰ (ethyl (2R,3S)-2-amino-3-hydroxy-3-(4-(methylsulfonyl)phenyl)propionate) is subjected to reduction reaction under the action of a reducing agent to obtain compound Ⅱ ((1R,2S)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol); and then compound Ⅲ ((4R,5R)-2-(1,1-dichloromethyl)-4-hydroxymethyl-5-(4-methylsulfonylphenyl)-4,5-oxazoline) is prepared through a cyclization reaction.

[0009] The reducing agent is selected from potassium borohydride or sodium borohydride.

[0010] The specific method is as follows:

[0011] (1) Reduction reaction

[0012] Take compound I, add solvent, stir to dissolve, and then cool the reaction solution to -10~0°C; then add reducing agent in portions, and control the temperature of the reaction solution not to exceed 5°C; after adding the reducing agent, stir at 0~5°C for 0.5~1h; then raise the temperature of the reaction solution to react; TLC monitors the complete reaction of compound I; after the reaction is completed, recover the solvent, add saturated ammonium chloride aqueous solution and ethyl acetate, extract and separate the liquids; the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness to obtain compound II.

[0013] (2) Cyclization reaction

[0014] Dissolve compound II in an alcohol solvent, then add concentrated hydrochloric acid, stir evenly and then add dichloroacetonitrile; then heat to react, and monitor the complete reaction of compound II by TLC; after the reaction is completed, add water to the reaction solution and stir to crystallize for 0.5-1h; filter, wash the filter cake with ice water, and dry to obtain the florfenicol intermediate (compound III).

[0015] Preferably, the amount of the reducing agent used is 1-2 mol / mol based on the amount of compound I fed.

[0016] Preferably, the solvent for the reduction reaction is anhydrous ethanol; the amount of anhydrous ethanol used is 5-10 mL / g based on the amount of compound I fed.

[0017] Preferably, the reduction reaction temperature is 15-60°C.

[0018] Preferably, the feeding amount of dichloroacetonitrile is 1.1-1.5 mol / mol based on the feeding amount of compound II.

[0019] Preferably, the amount of methanol used is 3-5 mL / g based on the amount of compound II fed.

[0020] Preferably, the cyclization reaction temperature is 35-60°C.

[0021] The beneficial effects of the present invention are:

[0022] The preparation method of the florfenicol intermediate provided by the present invention is simple, the starting raw materials are simple and easy to obtain, and the product can be obtained only through the steps of reduction and cyclization. At the same time, after multiple batches of amplification tests, the yield and purity of the product remain stable, and it is suitable for industrial production. DETAILED DESCRIPTION

[0023] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0024] Example 1

[0025] A method for preparing a florfenicol intermediate, the specific method is as follows:

[0026] (1) Reduction reaction

[0027] Take 10.0 g of compound I, add 50 mL of anhydrous ethanol, stir to dissolve, and then cool the reaction solution to -10°C; then add 2.82 g of potassium borohydride in 4 times, and control the temperature of the reaction solution not to exceed 5°C; after adding potassium borohydride, stir at 0~5°C for 0.5 h; then raise the temperature of the reaction solution to 40~45°C for reaction; TLC monitors the complete reaction of compound I; after the reaction is completed, recover the solvent, add 50 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate, extract and separate the liquids; the aqueous phase is back-extracted twice with 20 mL×2 of ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and evaporated to obtain 8.15 g of compound II, with a yield of 95.4%; HPLC: 99.64% (area normalized).

[0028] (2) Cyclization reaction

[0029] Dissolve 8.0 g of compound II in 30 mL of methanol, then add 0.8 g of concentrated hydrochloric acid, stir evenly and add 4.3 g of dichloroacetonitrile; then heat to 45-50 °C for reaction, and monitor the complete reaction of compound II by TLC; after the reaction, add 60 mL of water to the reaction solution and stir for crystallization for 1 h; filter, wash the filter cake with ice water, and dry to obtain 10.14 g of compound III, with a yield of 91.9%, HPLC: 98.44% (area normalized).

[0030] Example 2

[0031] A method for preparing a florfenicol intermediate, the specific method is as follows:

[0032] (1) Reduction reaction

[0033] Take 10.0 g of compound I, add 100 mL of anhydrous ethanol, stir to dissolve, and then cool the reaction solution to -10°C; then add 2.60 g of sodium borohydride in 4 times, and control the temperature of the reaction solution not to exceed 5°C; after adding sodium borohydride, stir at 0-5°C for 0.5 h; then raise the temperature of the reaction solution to 50-60°C for reaction; TLC monitors the complete reaction of compound I; after the reaction is completed, recover the solvent, add 50 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate, extract and separate the liquids; the aqueous phase is back-extracted twice with 20 mL×2 of ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and evaporated to obtain 7.96 g of compound II, with a yield of 93.2%; HPLC: 99.06% (area normalized).

[0034] (2) Cyclization reaction

[0035] Dissolve 7.5 g of compound II in 30 mL of methanol, then add 1.1 g of concentrated hydrochloric acid, stir evenly and add 5.0 g of dichloroacetonitrile; then heat to 55-60 °C for reaction, and monitor the complete reaction of compound II by TLC; after the reaction, add 60 mL of water to the reaction solution and stir for crystallization for 1 h; filter, wash the filter cake with ice water, and dry to obtain 9.34 g of compound III, with a yield of 90.3%, HPLC: 98.56% (area normalized).

[0036] Example 3

[0037] A method for preparing a florfenicol intermediate, the specific method is as follows:

[0038] (1) Reduction reaction

[0039] Take 100.0 g of compound I, add 500 mL of anhydrous ethanol, stir and dissolve, then cool the reaction solution to -10°C; then add 28.2 g of potassium borohydride in 6 times, and control the temperature of the reaction solution not to exceed 5°C; after adding potassium borohydride, stir at 0~5°C for 1 hour; then raise the temperature of the reaction solution to 45~50°C for reaction; TLC monitors the complete reaction of compound I; after the reaction is completed, recover the solvent, add 500 mL of saturated ammonium chloride aqueous solution and 500 mL of ethyl acetate, extract and separate the liquids; the aqueous phase is back-extracted three times with 150 mL×3 of ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and evaporated to obtain 81.6 g of compound II, with a yield of 95.6%; HPLC: 99.60% (area normalized).

[0040] (2) Cyclization reaction

[0041] Dissolve 80.0 g of compound II in 400 mL of methanol, then add 9.6 g of concentrated hydrochloric acid, stir evenly and add 43.0 g of dichloroacetonitrile; then heat to 50-55 °C for reaction, and monitor the complete reaction of compound II by TLC; after the reaction, add 800 mL of water to the reaction solution and stir for crystallization for 1 h; filter, wash the filter cake with ice water and dry to obtain 100.4 g of compound III, with a yield of 91.0%, HPLC: 98.79% (area normalized).

[0042] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily conceive of changes or substitutions within the technical scope disclosed by the present invention, and such changes or substitutions shall be within the scope of protection of the present invention.

Claims

1. A method for preparing a florfenicol intermediate, characterized in that: The reaction formula is as follows: ； The specific preparation method is as follows: (1) Reduction reaction Take compound I, add solvent, stir until dissolved, and then cool the reaction solution to -10~0°C; then add potassium borohydride or sodium borohydride as a reducing agent in portions, and control the temperature of the reaction solution not to exceed 5°C; after adding the reducing agent, stir at 0~5°C for 0.5~1h; then raise the temperature of the reaction solution to react; TLC monitors the complete reaction of compound I; after the reaction is completed, recover the solvent, add saturated ammonium chloride aqueous solution and ethyl acetate, extract and separate; the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness to obtain compound II; (2) Cyclization reaction Dissolve compound II in an alcohol solvent, then add concentrated hydrochloric acid, stir evenly, and then add dichloroacetonitrile; then heat to react, and monitor the complete reaction of compound II by TLC; after the reaction, add water to the reaction solution and stir to crystallize for 0.5-1h; filter, wash the filter cake with ice water, and dry to obtain a florfenicol intermediate; The cyclization reaction temperature is 35~60℃.

2. The method for preparing a florfenicol intermediate according to claim 1, wherein The amount of reducing agent used is 1-2 mol / mol based on the amount of compound I fed.

3. The method for preparing a florfenicol intermediate according to claim 1, wherein: The solvent for the reduction reaction is anhydrous ethanol.

4. The method for preparing a florfenicol intermediate according to claim 3, wherein: The amount of anhydrous ethanol used is 5-10 mL / g based on the amount of compound I added.

5. The method for preparing a florfenicol intermediate according to claim 1, wherein The reduction reaction temperature is 15~60℃.

6. The method for preparing a florfenicol intermediate according to claim 1, wherein: The amount of dichloroacetonitrile used is 1.1-1.5 mol / mol based on the amount of compound II fed.

7. The method for preparing a florfenicol intermediate according to claim 1, wherein: The amount of methanol used is 3-5 mL / g based on the amount of compound II.

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