Preparation method of sulfonamide intermediates for use in broad-spectrum veterinary and human drugs

Abstract

This invention relates to a method for preparing sulfonamide intermediates for broad-spectrum veterinary and human use, belonging to the field of pharmaceutical chemical technology. The method involves dissolving sulfadiazine in pyridine under stirring; adding acetic anhydride dropwise and then refluxing the mixture; after the reaction is complete, distilling under reduced pressure and precipitating the solid in ice water; filtering and washing with water until neutral to obtain a crude product; adding the crude product to a mixed solvent and heating to dissolve; adding activated carbon and hot filtering with stirring; cooling the filtrate and adding seed crystals and a sugar ester-sulfonamide composite crystallizing agent; continuing to cool and cultivate crystals; filtering, washing with cold ethanol, and vacuum drying to obtain the sulfonamide intermediate; the sugar ester-sulfonamide composite crystallizing agent is prepared by glucose pentaacetate, p-aminobenzenesulfonamide, pyridine, and boron trifluoride diethyl ether. This invention can obtain high-purity, stable, and regularly crystalline sulfonamide intermediates, providing a strong guarantee for the high-quality production of sulfonamide drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, and in particular to the preparation method of sulfonamide intermediates for use in both broad-spectrum veterinary and human drugs. Background Technology

[0002] Sulfonamides, as a class of chemically synthesized drugs with a broad antibacterial spectrum, have extremely important applications in both human and veterinary medicine. Their mechanism of action is mainly through inhibiting bacterial folic acid metabolism, thereby interfering with bacterial growth and reproduction. However, with the long-term and extensive use of sulfonamides, bacterial resistance has become an increasingly serious problem. To overcome this challenge, the development of novel and highly effective sulfonamides and the optimization of their synthetic processes are particularly urgent.

[0003] Chinese Patent CN117887031B, authorized by patent announcement number CN117887031B, provides a high molecular weight, highly biosafety-compliant sulfonamide polymer and its preparation method. The technical solution achieving the above objective is as follows: using polyethylene glycol and sulfonamide compounds as raw materials, under the catalysis of a green and non-toxic bismuth catalyst, they are coupled with hexamethylene diisocyanate to finally obtain a polyethylene glycol-sulfonamide copolymer.

[0004] Chinese patent application CN109796376A discloses a production process for sulfonamide intermediate amide-based benzenesulfonyl chloride. The process introduces a new solvent to dissolve raw material A, reducing the amount of chlorosulfonic acid (raw material B) used, ensuring complete reaction between raw material B and raw material A to obtain the amide-based benzenesulfonyl chloride.

[0005] Existing sulfonamide intermediates suffer from numerous problems, including low reactivity, cumbersome synthesis steps, high impurity content, and unstable crystal form. These issues not only increase drug production costs but may also affect drug efficacy and safety.

[0006] Therefore, developing a sulfonamide intermediate with high reactivity, easy synthesis, low impurity content, and stable crystal form, along with a matching efficient crystallization process, is of great practical significance for improving the quality and efficacy of sulfonamide drugs, reducing production costs, and minimizing environmental pollution. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a method for preparing a sulfonamide intermediate suitable for both broad-spectrum veterinary and human use, the steps of which are as follows:

[0008] Reflux reaction in S1: Add 70-100 parts of sulfadiazine to 200-300 parts of pyridine and stir until completely dissolved; slowly add 40-60 parts of acetic anhydride, controlling the temperature at 20-30℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove the pyridine by vacuum distillation, and pour the remaining material into 400-500 parts of ice water to precipitate the solid; filter, wash with water until neutral, and obtain the crude product;

[0009] S2 Crystallization Purification: Add the crude product to 300-400 parts of mixed solvent and heat to 60-70℃ to dissolve; add 5-10 parts of activated carbon, stir for 20-30 minutes, and remove carbon residue by hot filtration; cool the filtrate to 20-25℃, add 0.1-0.3 parts of seed crystals and 1-3 parts of sugar ester-sulfonamide composite crystallizing agent; continue to cool to 0-5℃ and grow crystals for 90-120 minutes; filter, wash with cold ethanol, and vacuum dry at 40-50℃ for 4-6 hours to obtain sulfonamide intermediates.

[0010] In some embodiments, the reflux reaction temperature in S1 is 80-85°C, and the reflux reaction time is 90-120 min.

[0011] In some embodiments, the S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0012] In some embodiments, the S2 seed crystal is N 4 - Acetylsulfadiazine.

[0013] In some embodiments, the cooling rate of S2 is 0.5-1℃ / min.

[0014] In some embodiments, the preparation method of the sugar ester-sulfonamide composite crystal former is as follows:

[0015] H1: Add 8-12 parts of glucose pentaacetate and 5-8 parts of p-aminobenzenesulfonamide to 30-40 parts of pyridine and mix under nitrogen protection; add 1-2 parts of boron trifluoride diethyl ether catalyst to carry out condensation reaction;

[0016] H2: After the reaction is complete, diethyl ether is added to precipitate the product and separate it from the reaction system; the precipitated product is dried to obtain the sugar ester-sulfonamide composite crystal agent.

[0017] In some embodiments, the temperature of the condensation reaction is 80-90°C, and the stirring reaction time is 6-8 hours.

[0018] Reaction Mechanism and Technical Effects: 1. When the two combine through a condensation reaction to form a sugar ester-sulfonamide composite crystal agent, a synergistic effect is produced. Among them, the glucose ring provides a rigid template structure, which can guide the sulfonamide intermediate to grow according to a specific crystal face, thereby forming a regular single crystal; while the sulfonamide group is tightly bound to the sulfonamide intermediate through hydrogen bonds, which plays a role in fixing the crystal structure and effectively preventing crystal transformation.

[0019] 2. This invention can obtain high-purity, stable and regular crystal sulfonamide intermediate crystals, providing a strong guarantee for the high-quality production of sulfonamide drugs. Detailed Implementation

[0020] To further illustrate the technical means and effects of the present invention in achieving the intended purpose, the following detailed description of the specific implementation methods, structures, features and effects of the present invention, in conjunction with preferred embodiments, is provided below.

[0021] Example 1: A method for preparing a sulfonamide intermediate suitable for both broad-spectrum veterinary and human use, comprising the following steps:

[0022] Reflux reaction in S1: Add 70g sulfadiazine to 200g pyridine and stir until completely dissolved; slowly add 40g acetic anhydride dropwise while controlling the temperature at 20℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove pyridine by vacuum distillation, and pour the remaining material into 400g ice water to precipitate solid; filter, wash with water until neutral, and obtain crude product;

[0023] S2 Crystallization Purification: Add the crude product to 300g of mixed solvent and heat to 60℃ to dissolve; add 5g of activated carbon, stir for 20 minutes, and remove carbon residue by hot filtration; cool the filtrate to 20℃, add 0.1g of seed crystals and 1g of sugar ester-sulfonamide composite crystallizing agent; continue to cool to 0℃ and grow crystals for 90 minutes; filter, wash with cold ethanol, and vacuum dry at 40℃ for 4 hours to obtain sulfonamide intermediates.

[0024] The reflux reaction temperature in S1 is 80°C, and the reflux reaction time is 90 min.

[0025] The S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0026] The S2 seed crystal is N 4 - Acetylsulfadiazine.

[0027] The cooling rate of S2 is 0.5℃ / min.

[0028] The preparation method of the sugar ester-sulfonamide composite crystal former is as follows:

[0029] H1: Add 8g of glucose pentaacetate (CAS No.: 604-68-2) and 5g of p-aminobenzenesulfonamide (CAS No.: 78-10-4) to 30g of pyridine and mix under nitrogen protection; add 1g of boron trifluoride diethyl ether catalyst to carry out condensation reaction;

[0030] H2: After the reaction is complete, diethyl ether is added to precipitate the product and separate it from the reaction system; the precipitated product is dried to obtain the sugar ester-sulfonamide composite crystal agent.

[0031] The condensation reaction temperature is 80℃, and the stirring reaction time is 6 hours.

[0032] Example 2: A method for preparing a sulfonamide intermediate suitable for both broad-spectrum veterinary and human use, comprising the following steps:

[0033] Reflux reaction in S1: Add 80g sulfadiazine to 240g pyridine and stir until completely dissolved; slowly add 45g acetic anhydride dropwise while controlling the temperature at 25℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove pyridine by vacuum distillation, and pour the remaining material into 440g ice water to precipitate solid; filter, wash with water until neutral, and obtain crude product;

[0034] S2 Crystallization Purification: The crude product was added to 340g of mixed solvent and heated to 65℃ to dissolve; 6g of activated carbon was added and stirred for 25 minutes, and the carbon residue was removed by hot filtration; the filtrate was cooled to 20℃, and 0.2g of seed crystals and 2g of sugar ester-sulfonamide composite crystallizing agent were added; the temperature was further cooled to 0℃ and crystallized for 100 minutes; the mixture was filtered, washed with cold ethanol, and vacuum dried at 45℃ for 5 hours to obtain sulfonamide intermediates.

[0035] The reflux reaction temperature in S1 is 80°C, and the reflux reaction time is 100 min.

[0036] The S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0037] The S2 seed crystal is N 4 - Acetylsulfadiazine.

[0038] The cooling rate of S2 is 0.6℃ / min.

[0039] The preparation method of the sugar ester-sulfonamide composite crystal former is as follows:

[0040] H1: 9g of glucose pentaacetate (CAS No.: 604-68-2) and 6g of p-aminobenzenesulfonamide (CAS No.: 78-10-4) were added to 33g of pyridine and mixed under nitrogen protection; 1.5g of boron trifluoride diethyl ether catalyst was added to carry out the condensation reaction;

[0041] H2: After the reaction is complete, diethyl ether is added to precipitate the product and separate it from the reaction system; the precipitated product is dried to obtain the sugar ester-sulfonamide composite crystal agent.

[0042] The condensation reaction temperature is 85℃, and the stirring reaction time is 7 hours.

[0043] Example 3: A method for preparing a sulfonamide intermediate suitable for both broad-spectrum veterinary and human use, comprising the following steps:

[0044] Reflux reaction in S1: Add 90g sulfadiazine to 280g pyridine and stir until completely dissolved; slowly add 55g acetic anhydride dropwise while controlling the temperature at 25℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove pyridine by vacuum distillation, and pour the remaining material into 480g ice water to precipitate solid; filter, wash with water until neutral, and obtain crude product;

[0045] S2 Crystallization Purification: The crude product was added to 380g of mixed solvent and heated to 65℃ to dissolve; 8g of activated carbon was added and stirred for 25 minutes, and the carbon residue was removed by hot filtration; the filtrate was cooled to 25℃, and 0.2g of seed crystals and 2g of sugar ester-sulfonamide composite crystallizing agent were added; the temperature was further reduced to 5℃ and crystallization was carried out for 110 minutes; the product was filtered, washed with cold ethanol, and vacuum dried at 45℃ for 5 hours to obtain sulfonamide intermediates.

[0046] The reflux reaction temperature in S1 is 85°C, and the reflux reaction time is 110 min.

[0047] The S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0048] The S2 seed crystal is N 4 - Acetylsulfadiazine.

[0049] The cooling rate of S2 is 0.8℃ / min.

[0050] The preparation method of the sugar ester-sulfonamide composite crystal former is as follows:

[0051] H1: 11g of glucose pentaacetate (CAS No.: 604-68-2) and 7g of p-aminobenzenesulfonamide (CAS No.: 78-10-4) were added to 38g of pyridine and mixed under nitrogen protection; 1.5g of boron trifluoride diethyl ether catalyst was added to carry out the condensation reaction.

[0052] H2: After the reaction is complete, diethyl ether is added to precipitate the product and separate it from the reaction system; the precipitated product is dried to obtain the sugar ester-sulfonamide composite crystal agent.

[0053] The condensation reaction temperature is 85℃, and the stirring reaction time is 7 hours.

[0054] Example 4: A method for preparing a sulfonamide intermediate suitable for both broad-spectrum veterinary and human use, comprising the following steps:

[0055] Reflux reaction in S1: Add 100g sulfadiazine to 300g pyridine and stir until completely dissolved; slowly add 60g acetic anhydride dropwise while controlling the temperature at 30℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove pyridine by vacuum distillation, and pour the remaining material into 500g ice water to precipitate solid; filter, wash with water until neutral, and obtain crude product;

[0056] S2 Crystallization Purification: The crude product was added to 400g of mixed solvent and heated to 70℃ to dissolve; 10g of activated carbon was added and stirred for 30 minutes, and the carbon residue was removed by hot filtration; the filtrate was cooled to 25℃, and 0.3g of seed crystals and 3g of sugar ester-sulfonamide composite crystallizing agent were added; the temperature was further reduced to 5℃ and crystallization was carried out for 120 minutes; the product was filtered, washed with cold ethanol, and vacuum dried at 50℃ for 6 hours to obtain sulfonamide intermediates.

[0057] The reflux reaction temperature in S1 is 85°C, and the reflux reaction time is 120 min.

[0058] The S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0059] The S2 seed crystal is N 4 - Acetylsulfadiazine.

[0060] The cooling rate of S2 is 1℃ / min.

[0061] The preparation method of the sugar ester-sulfonamide composite crystal former is as follows:

[0062] H1: 12g of glucose pentaacetate (CAS No.: 604-68-2) and 8g of p-aminobenzenesulfonamide (CAS No.: 78-10-4) were added to 40g of pyridine and mixed under nitrogen protection; 2g of boron trifluoride diethyl ether catalyst was added to carry out the condensation reaction.

[0063] H2: After the reaction is complete, diethyl ether is added to precipitate the product and separate it from the reaction system; the precipitated product is dried to obtain the sugar ester-sulfonamide composite crystal agent.

[0064] The condensation reaction temperature is 90℃, and the stirring reaction time is 8 hours.

[0065] Comparative Example 1: A method for preparing sulfonamide intermediates suitable for both broad-spectrum veterinary and human use, the steps of which are as follows:

[0066] Reflux reaction in S1: Add 70g sulfadiazine to 200g pyridine and stir until completely dissolved; slowly add 40g acetic anhydride dropwise while controlling the temperature at 20℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove pyridine by vacuum distillation, and pour the remaining material into 400g ice water to precipitate solid; filter, wash with water until neutral, and obtain crude product;

[0067] S2 crystallization purification: Add the crude product to 300g of mixed solvent and heat to 60℃ to dissolve; add 5g of activated carbon, stir for 20 minutes, and remove carbon residue by hot filtration; cool the filtrate to 20℃ and add 0.1g of seed crystals; continue to cool to 0℃ and grow crystals for 90 minutes; filter under vacuum, wash with cold ethanol, and dry under vacuum at 40℃ for 4 hours to obtain sulfonamide intermediates.

[0068] The reflux reaction temperature in S1 is 80°C, and the reflux reaction time is 90 min.

[0069] The S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0070] The S2 seed crystal is N 4 - Acetylsulfadiazine.

[0071] The cooling rate of S2 is 0.5℃ / min.

[0072] Comparative Example 2: A method for preparing sulfonamide intermediates suitable for both broad-spectrum veterinary and human use, the operation steps of which are as follows:

[0073] Reflux reaction in S1: Add 70g sulfadiazine to 200g pyridine and stir until completely dissolved; slowly add 40g acetic anhydride dropwise while controlling the temperature at 20℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove pyridine by vacuum distillation, and pour the remaining material into 400g ice water to precipitate solid; filter, wash with water until neutral, and obtain crude product;

[0074] S2 Crystallization Purification: Add the crude product to 300g of mixed solvent and heat to 60℃ to dissolve; add 5g of activated carbon, stir for 20 minutes, and remove carbon residue by hot filtration; cool the filtrate to 20℃, add 0.1g of seed crystals and 1g of crystallizing agent; continue to cool to 0℃ and grow crystals for 90 minutes; filter under vacuum, wash with cold ethanol, and dry under vacuum at 40℃ for 4 hours to obtain sulfonamide intermediates.

[0075] The reflux reaction temperature in S1 is 80°C, and the reflux reaction time is 90 min.

[0076] The S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0077] The S2 seed crystal is N 4 - Acetylsulfadiazine.

[0078] The cooling rate of S2 is 0.5℃ / min.

[0079] The crystallizing agent is glucose pentaacetate.

[0080] Comparative Example 3: A method for preparing sulfonamide intermediates suitable for both broad-spectrum veterinary and human use, the steps of which are as follows:

[0081] Reflux reaction in S1: Add 70g sulfadiazine to 200g pyridine and stir until completely dissolved; slowly add 40g acetic anhydride dropwise while controlling the temperature at 20℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove pyridine by vacuum distillation, and pour the remaining material into 400g ice water to precipitate solid; filter, wash with water until neutral, and obtain crude product;

[0082] S2 Crystallization Purification: Add the crude product to 300g of mixed solvent and heat to 60℃ to dissolve; add 5g of activated carbon, stir for 20 minutes, and remove carbon residue by hot filtration; cool the filtrate to 20℃, add 0.1g of seed crystals and 1g of crystallizing agent; continue to cool to 0℃ and grow crystals for 90 minutes; filter under vacuum, wash with cold ethanol, and dry under vacuum at 40℃ for 4 hours to obtain sulfonamide intermediates.

[0083] The reflux reaction temperature in S1 is 80°C, and the reflux reaction time is 90 min.

[0084] The S2 mixed solvent is ethanol and water in a volume ratio of 4:1.

[0085] The S2 seed crystal is N 4 - Acetylsulfadiazine.

[0086] The cooling rate of S2 is 0.5℃ / min.

[0087] The crystallizing agent is p-aminobenzenesulfonamide.

[0088] 1. Purity detection: The purity of sulfonamide intermediate crystals was detected by high performance liquid chromatography (HPLC).

[0089] 2. Crystal form detection: X-ray diffraction (XRD) analysis method is used to detect the crystal form of sulfonamide intermediate crystals.

[0090] The test results of the various embodiments and comparative examples obtained by the above methods are shown in Table 1 below.

[0091] Table 1: Test results of each embodiment and comparative example

[0092]

[0093] Through data analysis of the above embodiments and comparative examples, the present invention can obtain sulfonamide intermediate crystals with high purity, good stability and regular crystal form, providing a strong guarantee for the high-quality production of sulfonamide drugs.

[0094] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing sulfonamide intermediates suitable for both broad-spectrum veterinary and human use, characterized in that: The operating steps are as follows, according to the mass fraction: Reflux reaction in S1: Add 70-100 parts of sulfadiazine to 200-300 parts of pyridine and stir until completely dissolved; slowly add 40-60 parts of acetic anhydride, controlling the temperature at 20-30℃; after the addition is complete, heat the reaction system and reflux the reaction; after the reaction is complete, remove the pyridine by vacuum distillation, and pour the remaining material into 400-500 parts of ice water to precipitate the solid; filter, wash with water until neutral, and obtain the crude product; S2 Crystallization Purification: Add the crude product to 300-400 parts of mixed solvent and heat to 60-70℃ to dissolve; add 5-10 parts of activated carbon, stir for 20-30 minutes, and remove carbon residue by hot filtration; cool the filtrate to 20-25℃, add 0.1-0.3 parts of seed crystals and 1-3 parts of sugar ester-sulfonamide composite crystallizing agent; continue to cool to 0-5℃ and grow crystals for 90-120 minutes; filter under vacuum, wash with cold ethanol, and vacuum dry at 40-50℃ for 4-6 hours to obtain sulfonamide intermediates; The sugar ester-sulfonamide composite crystal former is prepared by reacting glucose pentaacetate, p-aminobenzenesulfonamide, and boron trifluoride diethyl ether catalyst; The preparation method of the sugar ester-sulfonamide composite crystal former is as follows: H1: Add 8-12 parts of glucose pentaacetate and 5-8 parts of p-aminobenzenesulfonamide to 30-40 parts of pyridine and mix under nitrogen protection; add 1-2 parts of boron trifluoride diethyl ether catalyst to carry out condensation reaction; H2: After the reaction is complete, diethyl ether is added to precipitate the product and separate it from the reaction system; the precipitated product is dried to obtain the sugar ester-sulfonamide composite crystal agent.

2. The method for preparing the broad-spectrum sulfonamide intermediate for both veterinary and human use according to claim 1, characterized in that: The reflux reaction temperature in S1 is 80-85℃, and the reflux reaction time is 90-120 min.

3. The method for preparing the broad-spectrum sulfonamide intermediate for both veterinary and human use according to claim 1, characterized in that: The S2 mixed solvent is ethanol and water in a volume ratio of 4:

1.

4. The method for preparing the broad-spectrum sulfonamide intermediate for both veterinary and human use according to claim 1, characterized in that: The S2 seed crystal is N 4 - Acetylsulfadiazine.

5. The method for preparing the broad-spectrum sulfonamide intermediate for both veterinary and human use according to claim 1, characterized in that: The cooling rate of S2 is 0.5-1℃ / min.

6. The method for preparing the broad-spectrum sulfonamide intermediate for both veterinary and human use according to claim 1, characterized in that: The condensation reaction temperature is 80-90℃, and the stirring reaction time is 6-8 hours.

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