A method for preparing a ceftiofur intermediate

Abstract

The application belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of a cefetico intermediate. The intermediate is 2-furan thio carboxylic acid, and the specific preparation steps are as follows: under nitrogen protection, 2-furan formyl chloride is reacted with potassium thioacetate in an organic solvent to generate a crude product or filtrate containing 2-furan formyl thioacetate; the crude product or filtrate containing 2-furan formyl thioacetate is hydrolyzed with a base in an alcohol solvent, and then the reaction system is acidified to pH 2-4 with an acid to obtain 2-furan thio carboxylic acid. The preparation method of the cefetico intermediate 2-furan thio carboxylic acid in the application uses potassium thioacetate as a sulfuration reagent, the thioacetate has strong nucleophilicity and good reactivity, the problem of by-product disulfide in the traditional process is solved, the problem of odor caused by the generation of disulfide in the traditional process can be effectively avoided, and the purity and yield of the final product are improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a method for preparing 2-furan thiocarboxylic acid, an intermediate of ceftiofur. Background Technology

[0002] 2-Furfural thiocarboxylic acid (CAS No. 4741-45-1, molecular formula C5H4O2S) possesses both an electron-rich furan ring and a highly reactive thiocarboxyl group, making it a key building block for the synthesis of various fine chemicals. Most importantly, 2-furanthiocarboxylic acid is the core side-chain intermediate for the synthesis of ceftiofur, a third-generation veterinary cephalosporin. Ceftiofur, with its broad-spectrum and highly effective antibacterial activity, is widely used in animal husbandry to treat respiratory diseases in cattle, pigs, and other animals, resulting in a huge market demand. Developing an economical, green, and industrially scalable synthetic route for high-purity 2-furanthiocarboxylic acid is crucial for ensuring a stable supply of ceftiofur and reducing its production costs.

[0003] Currently, the published synthetic routes for 2-furanthiocarboxylic acids are mainly based on the reaction of 2-furancarboxyl chloride with sulfur-containing nucleophiles. However, these methods generally have drawbacks. Patent US2003 / 216567A1 discloses a method involving the dropwise addition of 2-furancarboxyl chloride to an aqueous solution of sodium sulfide (Na₂S), followed by acidification to obtain the product. A significant drawback of this method is that the Na₂S used is readily oxidized by air in aqueous solution to form polysulfides (such as Na₂S₂, Na₂S₂). x Impurities such as acetyl chloride and methyl sulfide (MSC) have poor selectivity when reacting with acyl chloride, easily leading to side reactions and generating impurities such as disulfides, which seriously reduce the purity and yield of the target product. The reaction is carried out in an aqueous system, and acyl chloride is prone to hydrolysis side reactions, resulting in raw material loss and reduced yield. The reaction process generates a large amount of inorganic salts (such as NaCl), increasing the difficulty of post-processing and the cost of wastewater treatment. The reaction may release malodorous and toxic gases such as hydrogen sulfide (H2S), and there are safety hazards.

[0004] Patent CN117964641A discloses a route for reacting sodium hydrosulfide (NaSH) with furfuryl chloride (i.e., 2-furanoyl chloride) in an organic solvent (such as ethyl acetate). The main drawbacks of this method are: NaSH itself is unstable and easily decomposes and oxidizes in humidity and air, producing polysulfides and disulfides, which affect product purity; to inhibit the oxidation and hydrolysis of NaSH, precise control of anhydrous conditions is usually required, placing high demands on equipment and operation; as described in the patent, the dropwise addition of acyl chloride is an exothermic reaction, and if the temperature is not properly controlled (e.g., exceeding 60°C), impurities will increase significantly, and gases with irritating odors (mainly H2S) will be released, posing safety and environmental problems.

[0005] Patent CN119930551A discloses the reaction of sodium bisulfite (NaHSO3) aqueous solution with 2-furanoyl chloride. The main drawbacks of this method are: NaHSO3, as a nucleophile, has relatively weak nucleophilicity of its sulfur atom, and its reactivity and selectivity with acyl chloride may be inferior to those of hydrides, leading to incomplete reaction or slow rate; the reaction is carried out in the aqueous phase, so the risk of hydrolysis of acyl chloride still exists; and the atom economy of this reaction route is not high.

[0006] In summary, existing methods for synthesizing 2-furanthiocarboxylic acids generally suffer from numerous side reactions (especially the formation of disulfides), poor reaction selectivity, low product purity, stringent operating conditions (strict control of anhydrous and low temperature), low atom economy, and the potential generation of malodorous or harmful gases, making it difficult to meet the stringent quality requirements of the pharmaceutical industry for key intermediates.

[0007] Therefore, there is an urgent need in the field to develop a new synthetic method that can overcome the shortcomings of the existing technology and provide a preparation process for 2-furan thiocarboxylic acid with high yield, high purity, simple operation, environmental friendliness and greater suitability for large-scale industrial production. Summary of the Invention

[0008] To overcome the shortcomings of the prior art, the present invention provides a method for preparing 2-furan thiocarboxylic acid, an intermediate of ceftiofur.

[0009] The technical solution adopted in this invention is as follows:

[0010] A method for preparing a ceftiofur intermediate, wherein the intermediate is 2-furan thiocarboxylic acid, and the specific preparation steps are as follows:

[0011] (1) Under nitrogen protection, in an organic solvent, 2-furanoyl chloride reacts with potassium thioacetate to produce a crude product or filtrate containing 2-furanoyl thioacetate;

[0012] (2) The crude product or filtrate containing 2-furanoyl thioacetic acid ester is hydrolyzed with alkali in an alcohol solvent, and then the reaction system is acidified to pH 2-4 to obtain 2-furanoyl thiocarboxylic acid.

[0013] The organic solvent is ethyl acetate, tetrahydrofuran, or toluene; the mass ratio of the organic solvent added to 2-furanoyl chloride is (3.5~8):1.

[0014] Preferably, the organic solvent is ethyl acetate, and the mass ratio of the amount of ethyl acetate added to 2-furanoyl chloride is (4.5~6):1.

[0015] The molar ratio of 2-furanoyl chloride to potassium thioacetate is 1:(1.0~1.3).

[0016] The alcohol solvent is methanol, ethanol, or isopropanol.

[0017] The alkali is sodium hydroxide or potassium hydroxide, and the molar ratio of alkali to 2-furanoyl chloride is (1.0~1.5):1; the alkali is prepared as an aqueous solution with a concentration of 1-4M when used.

[0018] The hydrolysis reaction is carried out at a temperature of 20-60℃ for 1-4 hours.

[0019] The acid is concentrated hydrochloric acid, sulfuric acid, or phosphoric acid, preferably concentrated hydrochloric acid.

[0020] The acidification process is carried out under ice-water bath cooling, with the temperature controlled below 15°C.

[0021] The specific process of step (1) is as follows: potassium thioacetate is suspended in an organic solvent and stirred at 40-45℃ and 300-600 rpm for 2-3 hours. Then, 2-furanoyl chloride is slowly added dropwise at a rate of 0.5-2.0 mL / min·g. After the addition is complete, the reaction continues for 2-3 hours. After the reaction is completed, the mixture is cooled to room temperature and the solid byproducts are removed by filtration. The crude product or filtrate containing 2-furanoyl thioacetate is used directly for hydrolysis reaction.

[0022] In step (2), after the acidification process is completed, the acidified system is extracted with ethyl acetate, the organic phases are combined, and after washing, drying and vacuum concentration, 2-furanthiocarboxylic acid is obtained.

[0023] In this invention, room temperature is defined as 20-25°C.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The method for preparing the ceftiofur intermediate 2-furanthiocarboxylic acid of the present invention uses potassium thioacetate as a sulfiding agent, and thioacetate (AcS) - It exhibits strong nucleophilicity and good reactivity, solving the problem of disulfide byproducts in traditional processes. It can effectively avoid the odor problem caused by sulfides that may be generated in traditional processes, thereby improving the purity and yield of the final product.

[0026] (2) The inorganic salt byproduct generated by the preparation method of the present invention is mainly potassium chloride. Potassium chloride has high solubility in water but low solubility in alcohol. The process is easy to filter out the byproduct, reducing the separation difficulty and reducing the cost of wastewater treatment.

[0027] (3) The preparation method of the present invention has mild reaction conditions, significantly improved process stability, and increased process yield by about 8-10%. The product 2-furanthiocarboxylic acid is easier to purify and process, and the obtained 2-furanthiocarboxylic acid product has higher purity. Attached Figure Description

[0028] Figure 1 The liquid chromatogram of 2-furanthiocarboxylic acid obtained in Example 1 is shown below.

[0029] Figure 2 The liquid chromatogram of 2-furanthiocarboxylic acid obtained in Example 2;

[0030] Figure 3 The liquid chromatogram of 2-furanthiocarboxylic acid obtained in Example 3;

[0031] Figure 4 The liquid chromatogram of 2-furan thiocarboxylic acid obtained in Example 4 is shown. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand the present invention, but it is not intended to limit the present invention.

[0033] Unless otherwise specified, the experimental materials and reagents used in the embodiments of this invention are all consumables and reagents that are conventionally available from commercial sources.

[0034] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. Percentages and parts are by weight.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0036] In this embodiment of the invention, the concentrated hydrochloric acid used is hydrochloric acid with a mass percentage concentration of 36%-38%.

[0037] In this invention, the HPLC purity detection conditions are as follows: chromatographic column: C18 reversed-phase column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile / 0.1% phosphoric acid aqueous solution = 50 / 50 (v / v); flow rate: 1.0 mL / min; detection wavelength: 254 nm; column temperature: 30 °C; injection volume: 10 μL. Purity is calculated using the area normalization method.

[0038] In this invention, the TLC monitoring conditions are as follows: thin-layer plate: silica gel GF254 plate; developing solvent: petroleum ether / ethyl acetate = 3 / 1 (v / v); colorimetric method: inspection under a UV lamp at 254 nm.

[0039] Example 1

[0040] (1) A 2000mL four-necked flask equipped with a stirrer, a constant pressure dropping funnel, a thermometer, and nitrogen protection was used to add potassium thioacetate (156.0g, 1.366mol) and 800mL of anhydrous ethyl acetate. The stirring was started (500rpm) to form a suspension. The suspension was heated to 40℃ and stirred for 2 hours. Then, 2-furanoyl chloride (150.0g, 1.149mol) was added dropwise through the dropping funnel at a rate of 0.8mL / min·g. The temperature and stirring speed remained constant during the addition. After the addition was complete, the reaction was stirred at 40℃ for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and potassium chloride was filtered out. The residue was washed with warm ethyl acetate (about 30mL×2). The filtrates were combined. The filtrate contained 2-furanoyl thioacetate and was used directly in the next step of the reaction.

[0041] (2) Add the above filtrate to 600 mL of methanol, and slowly add 685 mL of 2M sodium hydroxide aqueous solution dropwise while stirring at room temperature. After the addition is complete, heat the reaction solution to 40 °C and stir at this temperature for 2 hours. Monitor the disappearance of the intermediate point by TLC (under the same conditions as above); cool the reaction solution to room temperature. Under ice-water bath cooling (<10 °C), slowly add concentrated hydrochloric acid until pH=2, transfer to a 2000 mL separatory funnel, add 300 mL of ethyl acetate, shake thoroughly, allow to stand for separation, and collect the organic phase. Extract the aqueous phase twice with ethyl acetate (300 mL × 2). Combine all organic phases and wash once with 200 mL of saturated sodium chloride solution. Transfer the organic phase to an Erlenmeyer flask, add anhydrous sodium sulfate (30-50 g) to dry, and let stand for 30 minutes until the liquid is clear. The dried organic phase was filtered, and the filtrate was concentrated under reduced pressure in a water bath at 35-40℃ using a rotary evaporator. Ethyl acetate was evaporated to obtain 128.9 g of a pale yellow to off-white solid. HPLC analysis showed that the purity was ≥99.0%, and the yield was 87.6% based on 2-furanoyl chloride.

[0042] This example uses approximately 1.19 equivalents of alkali to ensure complete hydrolysis. Good results can be obtained with alkali equivalents in the range of 1.0-1.2.

[0043] Example 2

[0044] (1) A 1000 mL four-necked flask equipped with a stirrer, a constant pressure dropping funnel, a thermometer, and nitrogen protection was used to add potassium thioacetate (62.4 g, 0.547 mol) and tetrahydrofuran (400 mL). The mixture was stirred at 400 rpm to form a suspension. The suspension was heated to 45 °C and stirred for 2 hours. Then, 2-furanoyl chloride (60.0 g, 0.460 mol) was slowly added dropwise at a rate of 1.0 mL / min·g. The temperature and stirring speed were kept constant during the addition. After the addition was complete, the mixture was stirred at 45 °C for 2.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with tetrahydrofuran (2 × 15 mL). The filtrates were combined and concentrated under reduced pressure to remove most of the tetrahydrofuran, yielding an oily crude product containing 2-furanoyl thioacetate.

[0045] (2) The crude product was dissolved in methanol (250 mL) and 4M sodium hydroxide aqueous solution (138 mL, 0.552 mol) was added dropwise under stirring at room temperature. After the addition was complete, the mixture was stirred at 25 °C for 3 hours. The reaction was monitored by TLC until complete (under the same conditions as above). The reaction solution was cooled to room temperature, and the subsequent acidification, extraction, washing, drying and concentration operations were the same as in Example 1, yielding 50.1 g of a pale yellow to off-white solid. HPLC analysis showed a purity ≥99.0% and a yield of 85.0% based on 2-furanoyl chloride.

[0046] Example 3

[0047] (1) The filtrate was prepared according to the method of Example 1, and the filtrate contained 2-furanoyl thioacetate (at a scale of 30.0 g of 2-furanoyl chloride and 0.230 mol).

[0048] (2) The obtained filtrate was mixed with ethanol (150 mL), and 2M potassium hydroxide aqueous solution (115 mL, 0.230 mol) was added dropwise under stirring at room temperature. After the addition was complete, the reaction solution was heated to 60 °C and stirred at this temperature for 1.5 hours (the reaction was monitored by TLC until complete, under the same conditions as above). After cooling, the pH was adjusted to 3 with concentrated sulfuric acid under an ice-water bath. The subsequent extraction, washing, drying and concentration operations were the same as in Example 1, yielding 25.0 g of 2-furanthiocarboxylic acid. HPLC analysis showed a purity ≥99.0% and a yield of 84.8% based on 2-furancarboxyl chloride.

[0049] Example 4

[0050] (1) A 2000 mL four-necked flask equipped with a stirrer, a constant pressure dropping funnel, a thermometer, and nitrogen protection was used to add potassium thioacetate (158.0 g, 1.39 mol) and toluene (1200 mL). The mixture was stirred at 350 rpm to form a suspension. The suspension was heated to 45 °C and stirred for 2 hours. Then, 2-furanoyl chloride (150.0 g, 1.15 mol) was slowly added dropwise at a rate of 1.8 mL / min·g, while maintaining a constant temperature and stirring speed. After the addition was complete, the mixture was stirred at 45 °C for another 2.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with toluene. The filtrates were combined. The filtrate contained 2-furanoyl thioacetate and was used directly in the next step of the reaction.

[0051] (2) Add isopropanol (600 mL) to the filtrate, and add 3M sodium hydroxide aqueous solution (460 mL, 1.38 mol) dropwise while stirring at room temperature. After the addition is complete, heat the reaction solution to 40 °C and stir at this temperature for 2 hours. Monitor the disappearance of the intermediate point by TLC (under the same conditions as above); cool the reaction solution to room temperature. Adjust the pH to 3 with concentrated hydrochloric acid in an ice-water bath. Transfer to a separatory funnel, separate the aqueous phase, wash the organic phase with water (200 mL) and saturated brine (200 mL), and dry with anhydrous magnesium sulfate. Filter, concentrate under reduced pressure, and obtain 126.5 g of 2-furanthiocarboxylic acid. HPLC analysis shows a purity ≥99.0% and a yield of 85.9% based on 2-furancarboxyl chloride.

[0052] While the specific embodiments of the present invention have been described above, they are not intended to limit the scope of protection of the present invention. Based on the technical solutions of the present invention, various modifications or variations that can be made by those skilled in the art without creative effort are still within the scope of protection of the present invention.

Claims

1. A method for preparing a ceftiofur intermediate, characterized in that, The intermediate is 2-furan thiocarboxylic acid, and the specific preparation steps are as follows: (1) Under nitrogen protection, in an organic solvent, 2-furanoyl chloride reacts with potassium thioacetate to produce a crude product or filtrate containing 2-furanoyl thioacetate; (2) The crude product or filtrate containing 2-furanoyl thioacetic acid ester is hydrolyzed with alkali in an alcohol solvent, and then the reaction system is acidified to pH 2-4 to obtain 2-furanoyl thiocarboxylic acid.

2. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The organic solvent is ethyl acetate, tetrahydrofuran, or toluene.

3. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The mass ratio of the added organic solvent to 2-furanoyl chloride is (3.5~8):

1.

4. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The molar ratio of 2-furanoyl chloride to potassium thioacetate is 1:(1.0~1.3).

5. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The alcohol solvent is methanol, ethanol, or isopropanol.

6. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The alkali is sodium hydroxide or potassium hydroxide; the molar ratio of alkali to 2-furanoyl chloride is (1.0~1.5):1; the alkali is prepared as an aqueous solution with a concentration of 1-4M when used.

7. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The hydrolysis reaction is carried out at a temperature of 20-60℃ for 1-4 hours.

8. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The acid is concentrated hydrochloric acid, sulfuric acid, or phosphoric acid.

9. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, The acidification process is controlled at a temperature below 15°C.

10. The method for preparing the ceftiofur intermediate according to claim 1, characterized in that, Step (1) specifically includes: suspending potassium thioacetate in an organic solvent, stirring at 40-45℃ and 300-600 rpm for 2-3 hours, then slowly adding 2-furanoyl chloride at a rate of 0.5-2.0 mL / min·g, continuing the reaction for 2-3 hours after the addition is complete, cooling to room temperature after the reaction is complete, and filtering to remove solid byproducts.

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