Preparation method of sulfadimethoxine

Abstract

The invention provides a preparation method of sulfadimethoxine. The method is a preparation method of sulfadimethoxine, and 4, 6-dichloro-2-methoxyl pyrimidine and sulfadimethoxine sodium are used as raw materials to be subjected to condensation and methoxyl reaction to prepare a sulfadimethoxine product. The method has the advantages of simple process, no special requirements on equipment, simplicity and convenience in operation, good product quality and easiness in three-waste treatment, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of sulfonamide antibacterial drugs, and particularly relates to a method for preparing sulfadiazine. Background Art

[0002] Sulfadimethoxypyrimidine is also known as sulfadimethoxypyrimidine, English name: Sulfadimethoxypyrimidine, chemical name: 4-(p-aminobenzenesulfonylamino)-2,6-dimethoxypyrimidine, CAS registration number: 122-11-2, chemical structure formula is as follows:

[0003] Sulfadimethoxine belongs to the sulfonamide antibacterial drugs. Because of its strong anti-bacterial and protozoal effects, it is currently widely used in the treatment and prevention of livestock and poultry diseases. Due to its growth-promoting effect, it is also widely used as a feed additive in livestock and poultry breeding. The main production process currently used is: 4-amino-2,6-dimethoxypyrimidine formula 5 and 4-acetylaminobenzenesulfonyl chloride formula 6 are condensed to obtain acetylsulfadimethoxine formula 7, and then the acetyl group is hydrolyzed to obtain sulfadimethoxine formula 1. The main reaction formula is as follows:

[0004] Disadvantages of this process: 1) The starting material 4-amino-2,6-dimethoxypyrimidine is relatively expensive. In order to improve the conversion rate of 4-amino-2,6-dimethoxypyrimidine, the amount of 4-acetylaminobenzenesulfonyl chloride added is increased in production, resulting in a large excess of 4-acetylaminobenzenesulfonyl chloride. This results in the generation of a disubstituted impurity of formula 8 on the amino group of the pyrimidine ring, which is relatively large, often exceeding 0.5%. This impurity is difficult to remove in subsequent reactions, often resulting in poor product quality;

[0005] 2) A large amount of pyridine is used in the condensation reaction. Pyridine is expensive and tastes unfriendly to the human body. It is difficult to recycle and reuse. The amount of three wastes is large and difficult to treat. 3) The starting material, 4-acetamidobenzenesulfonyl chloride, easily absorbs moisture and causes decomposition, and is not suitable for long-term storage. In addition, the quality of chemical-grade products is unstable, and the appearance of the same batch varies greatly, making it difficult to control the quality of subsequent products; 4) The acetyl group may not be completely removed during the hydrolysis of acetylsulfadiazine, and it is difficult to completely remove it during the post-treatment process, resulting in a large amount of residue in the final product, often exceeding 0.1% or even 1.0%.

[0006] Therefore, it is very necessary to develop a new synthetic route for sulfadiazine with high quality, high yield and low cost. Summary of the invention

[0007] The technical problem to be solved by the present invention is a method for preparing sulfadiazocine, which solves the defects of the existing process such as complex operation, poor product quality and difficulty in treating three wastes.

[0008] 1) A method for preparing sulfadimethoxine 1, characterized in that 4,6-dichloro-2-methoxypyrimidine 3 and sodium sulfonamide 4 are subjected to a condensation reaction under an acid-binding agent to obtain a condensate 2, and the condensate is subjected to a methoxylation reaction under alkaline conditions to obtain sulfadimethoxine 1; the reaction formula is as follows:

[0009] 2) The method according to claim 1, characterized in that: the condensation reaction solvent is one of N,N-dimethylformamide or N,N-dimethylacetamide.

[0010] 3) The method according to claim 1, characterized in that the condensation reaction temperature is 80°C to 120°C.

[0011] 4) The method according to claim 1, characterized in that the molar ratio of the 4,6-dichloro-2-methoxypyrimidine formula 3 to the sodium sulfonamide formula 4 is 1:(1.0-2.0).

[0012] 5) The method according to claim 1, characterized in that the weight ratio of the 4,6-dichloro-2-methoxypyrimidine formula 3 to the reaction solvent is 1:(4.0-8.0).

[0013] 6) The method according to claim 1, characterized in that the acid binding agent is one of sodium carbonate, potassium carbonate or sodium sulfonamide formula 4.

[0014] 7) The method according to claim 1, characterized in that the weight ratio of the condensation product of formula 2 to the reaction solvent is 1:(4.0-10.0).

[0015] 8) The method according to claim 1, characterized in that: the methoxidation alkaline condition is one of sodium hydroxide or sodium methoxide.

[0016] 9) The method according to claim 8, characterized in that the molar ratio of the condensation product of formula 2 to sodium hydroxide or sodium methoxide is 1:(2.0-5.0).

[0017] 10) The method according to claim 1, characterized in that the methoxylation reaction temperature is 60°C to 80°C.

[0018] The advantages of the present invention are as follows: 1) Compared with the existing process, the sulfadiazocine obtained by the preparation method of the present invention has easy-to-obtain raw material sources, stable quality and high yield.

[0019] 2) Compared with the method in the prior art, the preparation method of the present invention eliminates the use of pyridine and is easier to treat the three wastes.

[0020] 3) Compared with the method in the prior art, the preparation method of the present invention avoids the possibility of generating the disubstituted impurity formula 8 of the amino group on the pyrimidine ring because acetylaminobenzenesulfonyl chloride is not used.

[0021] 4) Compared with the method in the prior art, the preparation method of the present invention does not have the step of hydrolysis and deacetylation, thereby avoiding the generation of acetylsulfadiazine formula 7 impurity. Meanwhile, other impurities are also below 0.1%, and the product purity is above 99.8% (normalized method).

[0022] 5) Compared with the methods in the prior art, the preparation method of the present invention has a simple process and operation process, has no special requirements on production equipment, and is suitable for industrial production.

[0023] The raw material 4,6-dichloro-2-methoxypyrimidine of formula 3 used in the present invention is easily obtained and can be prepared by methods disclosed in existing literature, such as WO2007 / 65940, etc. The reaction formula is as follows:

[0024] The raw material sodium sulfonamide of formula 4 used in the present invention is easily obtained and can be prepared by methods disclosed in existing literature, such as the National Medical and Pharmaceutical Administration. National Raw Material Drug Process Compilation, P172-175, etc., and its reaction formula is as follows:

[0025] The preparation method of the present invention is further described and explained by examples, but the scope of the present invention is not limited thereto. DETAILED DESCRIPTION

[0026] Example 1 Preparation of condensation product of formula 2 In a reaction flask, add 716.0 g of N,N-dimethylformamide (DMF, the same below), 497.1 g (0.5 mol) of sodium sulfonamide, 106.0 g (0.5 mol) of sodium carbonate and 389.5 g (0.5 mol) of 4,6-dichloro-2-methoxypyrimidine respectively, heat to 120°C and react for 3 hours, distill off the solvent under reduced pressure, add water to dissolve, adjust the pH to neutral with hydrochloric acid, cool, filter, recover 9.0 g of sulfonamide, adjust the pH of the filtrate to 3.8-4.1 with hydrochloric acid, filter, and dry to obtain condensate 2129.5 g with a yield of 82.3%.

[0027] Example 2 Preparation of Condensate Formula 2 In a reaction flask, 573.0 g of N,N-dimethylacetamide (DMA, the same below) 4315.0 g (1.6 mol) of sodium sulfonamide and 3143.2 g (0.8 mol) of 4,6-dichloro-2-methoxypyrimidine were added respectively, and the mixture was heated to 100°C for reaction for 5 hours. The solvent was distilled off under reduced pressure, and water was added to dissolve the mixture. The pH was adjusted to neutral with hydrochloric acid, and the mixture was cooled and filtered to recover 120.0 g of sulfonamide. The pH of the filtrate was adjusted to 3.8-4.1 with hydrochloric acid, and the mixture was filtered and dried to obtain condensate 2214.7 g with a yield of 85.3%.

[0028] Example 3 Preparation of Condensate Formula 2 In a reaction bottle, add DMF 420.0g, potassium carbonate 82.8g (0.6mol), sodium sulfonamide 478.8g (0.4mol) and 4,6-dichloro-2-methoxypyrimidine 371.6g (0.4mol), respectively, heat to 80°C for 6 hours, distill off the solvent under reduced pressure, add water to dissolve, adjust the pH to neutral with hydrochloric acid, cool, filter, recover sulfonamide, adjust the pH of the filtrate to 3.8-4.1 with hydrochloric acid, filter, and dry to obtain condensate 2100.9g, with a yield of 80.1%. Example 4 Preparation of Sulfadimethoxine Formula 1 Add 630.0 g of methanol, 40.0 g (1.0 mol) of sodium hydroxide and 157.4 g (0.5 mol) of condensate to a reaction flask, heat to 60°C and react for 8 hours, distill off the solvent, add water and stir to dissolve, adjust the pH to 9-10 with dilute acetic acid, add activated carbon for decolorization, filter, adjust the pH of the filtrate to 6.5-7.0 with dilute acetic acid, filter, wash and dry to obtain 1139.7 g of sulfadimethoxine, with a yield of 90.0%; HPLC purity 99.87% (normalization method), acetylsulfadimethoxine 7 impurity was not detected, and disubstituted impurity 8 was not detected.

[0029] Example 5 Preparation of Sulfadimethoxine Formula 1 Add 2300.0 g of methanol, 864.3 g (4.8 mol) of 30% sodium methoxide and 2377.7 g (1.2 mol) of condensate formula into a reaction bottle, heat to 80°C for reaction for 5 hours, distill off the solvent, add water and stir to dissolve, adjust pH to 9-10 with dilute acetic acid, add activated carbon for decolorization, filter, adjust pH of the filtrate to 6.5-7.0 with dilute acetic acid, filter, wash and dry to obtain 345.6 g of sulfadimethoxine formula I, with a yield of 92.8%; HPLC purity 99.94% (normalization method), acetylsulfadimethoxine formula 7 impurity was not detected, and disubstituted impurity formula 8 was not detected.

[0030] Example 6 Preparation of Sulfadimethoxine Formula 1 Add 630.0 g of methanol, 40.0 g (1.0 mol) of sodium hydroxide and 63.0 g (0.2 mol) of condensate Formula 2 to a reaction flask, heat to 60°C for reaction for 10 hours, distill off the solvent, add water and stir to dissolve, adjust pH to 9-10 with dilute acetic acid, add activated carbon for decolorization, filter, adjust pH of the filtrate to 6.5-7.0 with dilute acetic acid, filter, wash and dry to obtain 154.7 g of sulfadimethoxine Formula, with a yield of 88.1%; HPLC purity 99.82% (normalization method), acetylsulfadimethoxine Formula 7 impurity was not detected, and disubstituted impurity Formula 8 was not detected.

[0031] Example 7 Preparation of Sulfadimethoxine Formula 1 1500.0 kg of methanol, 90.0 kg (2.25 kmol) of sodium hydroxide and 2300.0 kg (0.95 kmol) of condensate were added to the reaction tank respectively, heated to 80°C for reaction for 5 hours, the solvent was distilled off, water was added and stirred to dissolve, the pH was adjusted to 9-10 with dilute acetic acid, activated carbon was added for decolorization, and the mixture was filtered. The filtrate was adjusted to pH 6.5-7.0 with dilute acetic acid, filtered, washed, and dried to obtain 1275.4 kg of sulfadimethoxine, with a yield of 93.1%; HPLC purity was 99.95% (normalization method), acetylsulfadimethoxine impurity 7 was not detected, and disubstituted impurity 8 was not detected.

[0032] The present invention has been described in detail above, including its preferred embodiments. However, it should be understood that, considering the disclosure of the present invention, those skilled in the art may make changes and / or improvements to the present invention within the spirit of the claims, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing sulfadiazocine formula 1, Features A condensation reaction is carried out between 4,6-dichloro-2-methoxypyrimidine Formula 3 and sodium sulfonamide Formula 4 under an acid-binding agent to obtain a condensate Formula 2. The condensate Formula 2 is subjected to a methoxylation reaction under alkaline conditions to obtain sulfadimethoxine Formula 1. The reaction formula is as follows:

2. The method according to claim 1, Features: The condensation reaction solvent is one of N,N-dimethylformamide and N,N-dimethylacetamide.

3. The method according to claim 1, Features: The condensation reaction temperature is 80°C to 120°C.

4. The method according to claim 1, Features: The molar ratio of the 4,6-dichloro-2-methoxypyrimidine formula 3 to the sodium sulfonamide formula 4 is 1:(1.0-2.0).

5. The method according to claim 1, Features: The weight ratio of the 4,6-dichloro-2-methoxypyrimidine formula 3 to the reaction solvent is 1:(4.0-8.0).

6. The method according to claim 1, Features: The acid binding agent is one of sodium carbonate, potassium carbonate or sodium sulfonamide formula 4.

7. The method according to claim 1, Features: The weight ratio of the condensate of formula 2 to the reaction solvent is 1:(4.0-10.0).

8. The method according to claim 1, Features: The methoxidation alkaline condition is one of sodium hydroxide or sodium methoxide.

9. The method according to claim 8, Features: The molar ratio of the condensation product of formula 2 to sodium hydroxide or sodium methoxide is 1:(2.0-5.0).

10. The method according to claim 1, Features: The methoxidation reaction temperature is 60°C to 80°C.

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