A process for the synthesis of cefixime open loop side chain acid

Abstract

The application belongs to the field of medical intermediates, and discloses a synthesis process of cefixime ring-opening side chain acid, which comprises the following steps: dissolving a hydrocarbonate in an organic solvent, adding bromine and hydrogen peroxide drop by drop to carry out bromination and acidolysis deprotection reaction, keeping warm until the reaction is completed, cooling, and filtering to obtain the cefixime ring-opening side chain acid. In the application, hydrogen bromide generated in the bromination reaction is in-situ oxidized into bromine by hydrogen peroxide, so that the bromine can be recycled, and the application is green, high in yield and good in atomic economic benefit.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate preparation, specifically relating to a method for synthesizing cefixime open-chain side chain acid. Background Technology

[0002] Cefixime is a third-generation cephalosporin antibiotic, widely used due to its strong antibacterial effect, broad antibacterial spectrum, wide range of indications, good efficacy, and low dosage. The open-ring side chain acid of cefixime (structure shown in Formula I, where X is Br or Cl, and in the product of this invention, X is Br) is a key intermediate for cefixime, and its synthesis process has attracted much attention from researchers.

[0003]

[0004] Chinese patent application CN117510367A discloses a method for preparing cefixime open-ring side-chain acids. The method involves dissolving a hydrocarbon in an organic solvent, adding hydrogen chloride for acidolysis to obtain a solution containing an intermediate compound, adding a catalyst to the solution, then adding chlorine and hydrogen chloride for chlorination, followed by vacuum distillation, pulping, filtration, and vacuum drying to obtain the cefixime open-ring side-chain acid. Although this patent recycles the byproduct hydrogen chloride as a raw material, the reaction system is still an organic solvent system, resulting in large quantities of waste, high costs, and significant disposal difficulties.

[0005] Chinese patent application CN112624939A discloses a method for synthesizing the ring-opening side-chain acid of cefixime. The method employs a tandem batch reaction, in which hydrocarbons, a catalyst, acetic acid, and sulfonyl chloride are reacted under controlled temperature. Acetic acid is removed by vacuum distillation, the solid is poured into water to precipitate, cooled, and filtered to obtain the product. This patent application uses sulfonyl chloride as the chlorination acid hydrolysis reagent, which generates useless SO2 during the reaction, resulting in poor atom economy and significant environmental pressure.

[0006] Chinese patent application CN120483895A discloses a method for preparing cefixime ring-opening side-chain acids using an aqueous phase method. A hydrocarbon, catalyst, and citric acid solution are added to water to carry out a deprotection reaction, yielding an aqueous solution containing an intermediate compound and the catalyst. After cooling, an aqueous solution of N-chlorosuccinimide is added to carry out a chlorination reaction. The pH is adjusted with alkali, followed by extraction and separation to obtain an aqueous phase. Acid is added to the aqueous phase to adjust the pH, precipitating a solid, which is then filtered and vacuum dried to obtain the cefixime ring-opening side-chain acid. This patent application uses water as the solvent system to reduce acid gas emissions, but the post-processing uses solvent extraction, still resulting in VOCs volatilization. The subsequent acid and alkali adjustments in the post-processing, along with the need for desalination of the salt-containing wastewater, create significant environmental pressure during production.

[0007] Existing production processes for cefixime open-ring side-chain acids suffer from poor atom economy, low yield, and significant environmental impact. There is an urgent need to provide an environmentally friendly and low-cost method for preparing cefixime open-ring side-chain acids. Summary of the Invention

[0008] The purpose of this invention is to provide a synthetic process for the open-ring side chain acid of cefixime, which is environmentally friendly, has good atom economy, and high yield.

[0009] The synthesis process of cefixime open-ring side chain acid according to the present invention includes the following steps:

[0010] The hydrocarbon was dissolved in an organic solvent, and bromine and hydrogen peroxide were added dropwise simultaneously under stirring to carry out bromination and acid deprotection reactions. After the reaction was completed, the cefixime ring-opening side chain acid was obtained through post-treatment.

[0011] The reaction formula is as follows:

[0012]

[0013] The hydrogen bromide produced by the bromination reaction is oxidized in situ by hydrogen peroxide to bromine, thus achieving recycling.

[0014] The organic solvent is one or a mixture of two of acetic acid and acetonitrile, preferably acetic acid.

[0015] The weight ratio of the hydrocarbon to the organic solvent is 1:0.1~1.0, preferably 1:0.2~0.5.

[0016] The molar ratio of the hydrocarbon, bromine, and hydrogen peroxide (based on the amount of hydrogen peroxide) is 1:0.5~1.0:0.25~0.55, preferably 1:0.50~0.65:0.35~0.50.

[0017] The hydrogen peroxide has a mass percentage concentration of 25% to 50%, preferably 27.5%.

[0018] The reaction temperature is 20~50℃, preferably 35~45℃.

[0019] The bromine and hydrogen peroxide are added over a period of 2 to 8 hours, preferably 4 to 6 hours.

[0020] The bromination reaction and acid deprotection reaction also include a heat preservation reaction step, with a heat preservation reaction time of 1 to 6 hours, preferably 2 to 4 hours.

[0021] The cooling crystallization temperature is 0~20℃, preferably 5~15℃.

[0022] The reaction principle of this invention is as follows:

[0023]

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] Existing processes use sulfonyl chloride or chlorine gas for chloroacidolysis, which suffers from high acid gas treatment costs, low atom utilization, and the use of low-boiling-point solvents for pulping, resulting in significant VOC emissions and environmental pressure. This invention utilizes a combination of bromine and hydrogen peroxide to complete the bromination acidolysis reaction, resulting in high selectivity and yield. The hydrogen bromide produced after bromination is oxidized in situ by hydrogen peroxide, achieving bromine recycling, high atom utilization, and the use of high-boiling-point solvents, reducing environmental pressure from acid gas and VOC emissions, thus better aligning with green atom economics. Attached Figure Description

[0026] Figure 1 The liquid phase spectrum of the product obtained in Example 1 is shown.

[0027] Figure 2 The image shows the proton NMR spectrum of the product obtained in Example 1.

[0028] Figure 3 The liquid phase spectrum of the product obtained in Comparative Example 2 is shown. Detailed Implementation

[0029] The present invention will be further described below through specific embodiments and comparative examples.

[0030] The purity of the product obtained by this invention is the same as that obtained by the HPLC area normalization method.

[0031] Example 1

[0032] 60.6 g of hydrocarbon and 25 g of acetic acid were added to a reaction flask. The temperature was controlled at 40 °C. Simultaneously, 20.5 g of bromine and 13.5 g of 27.5% hydrogen peroxide were added dropwise under stirring for 4 hours. The mixture was kept at this temperature for 3 hours, then cooled to 5 °C and filtered to obtain a wet product of the open-ring side-chain acid of cefixime. The product was washed with ice water at 0–5 °C and then vacuum dried to obtain 63.6 g of the product. The molar yield was 96.5% (based on hydrocarbon) and the purity was 97.0% (see liquid chromatography chromatogram). Figure 1 Cefixime open-chain side chain acid 1 The H NMR spectrum is shown in [reference]. Figure 2 .That 1 The H NMR spectral parameters are: 1 HNMR(300 MHz, DMSO-d6) δ 3.69 (s, 3H), 3.91 (s, 2H), 4.78 (s, 2H), 12.56 (s,1H).

[0033] Example 2

[0034] 60.6 g of hydrocarbon and 25 g of acetic acid were added to a reaction flask. The temperature was controlled at 40 °C. Under stirring, 20.5 g of bromine and 13.5 g of 27.5% hydrogen peroxide were added dropwise over a period of 2 h. The mixture was kept at this temperature for 3 h, then cooled to 5 °C and filtered to obtain wet cefixime open-ring side-chain acid. The product was washed with ice water at 0-5 °C and then vacuum dried to obtain 63.3 g of product. The molar yield was 96.0% (based on hydrocarbon) and the purity was 95.9%.

[0035] Example 3

[0036] 60.6 g of hydrocarbon and 25 g of acetic acid were added to a reaction flask. The temperature was controlled at 40 °C. Under stirring, 18.7 g of bromine and 14.4 g of 27.5% hydrogen peroxide were added dropwise over a period of 4 h. The mixture was kept at this temperature for 3 h, cooled to 5 °C, and filtered to obtain wet cefixime open-ring side-chain acid. The product was washed with ice water at 0-5 °C and then vacuum dried to obtain 63.0 g of product. The molar yield was 95.6% (based on hydrocarbon) and the purity was 95.5%.

[0037] Example 4

[0038] 60.6 g of hydrocarbon and 25 g of acetonitrile were added to a reaction flask. The temperature was controlled at 45 °C. Under stirring, 20.5 g of bromine and 13.5 g of 27.5% hydrogen peroxide were added dropwise over a period of 4 h. The mixture was kept at this temperature for 3 h, then cooled to 5 °C and filtered to obtain wet cefixime open-ring side-chain acid. The product was washed with ice water at 0-5 °C and then vacuum dried to obtain 63.1 g of product. The molar yield was 95.7% (based on hydrocarbon) and the purity was 96.0%.

[0039] Example 5

[0040] 60.6 g of hydrocarbon and 25 g of acetonitrile were added to a reaction flask. The temperature was controlled at 45 °C. Under stirring, 20.5 g of bromine and 7.5 g of 50% hydrogen peroxide were added dropwise over a period of 4 h. The mixture was kept at this temperature for 3 h, then cooled to 5 °C and filtered to obtain wet cefixime open-ring side-chain acid. The product was washed with ice water at 0-5 °C and then vacuum dried to obtain 62.5 g of product. The molar yield was 94.8% (based on hydrocarbon) and the purity was 95.5%.

[0041] Comparative Example 1

[0042] Without adding hydrogen peroxide, the other operations were the same as in Example 1, to obtain the wet product of cefixime with open ring side chain acid. The product was washed with ice water at 0-5°C and then vacuum dried to obtain 31.0 g of product with a molar yield of 47.0% (based on hydrocarbons) and a purity of 75.0%.

[0043] Comparative Example 2

[0044] 60.6 g of hydrocarbon and 25 g of acetic acid were added to a reaction flask. The temperature was controlled at 40 °C. Under stirring, 20.5 g of bromine was added dropwise over a period of 5 h, followed by 13.5 g of 27.5% hydrogen peroxide over a period of 5 h. The mixture was kept at this temperature for 3 h, then cooled to 5 °C and filtered to obtain wet cefixime open-ring side-chain acid. The product was washed with ice water at 0-5 °C and then vacuum dried to obtain 42.6 g of product. The molar yield was 64.6% (based on hydrocarbon) and the purity was 81.9% (see liquid chromatography chromatogram). Figure 3 ).

Claims

1. A process for synthesizing cefixime ring-opening side chain acids, characterized in that, Includes the following steps: The hydrocarbon was dissolved in an organic solvent, and bromine and hydrogen peroxide were added dropwise simultaneously under stirring to carry out bromination and acid deprotection reactions. After the reaction was completed, the cefixime ring-opening side chain acid was obtained through post-treatment. The reaction formula is as follows: ； The hydrogen bromide produced by the bromination reaction is oxidized in situ by hydrogen peroxide to bromine, thus achieving recycling.

2. The synthesis process of cefixime ring-opening side chain acid according to claim 1, characterized in that, The organic solvent is one or a mixture of two of acetic acid and acetonitrile; The weight ratio of the hydrocarbon to the organic solvent is 1:0.1~1.

0.

3. The synthesis process of cefixime ring-opening side chain acid according to claim 2, characterized in that, The organic solvent is acetic acid; The weight ratio of the hydrocarbon to the organic solvent is 1:0.2~0.

5.

4. The synthesis process of cefixime ring-opening side chain acid according to claim 1, characterized in that, The molar ratio of the hydrocarbon, bromine, and hydrogen peroxide is 1:0.5~1.0:0.25~0.

55.

5. The synthesis process of cefixime ring-opening side chain acid according to claim 1, characterized in that, The hydrogen peroxide has a mass percentage concentration of 25% to 50%.

6. The synthesis process of cefixime ring-opening side chain acid according to claim 1, characterized in that, The bromination reaction and acid deprotection reaction are carried out at temperatures of 20~50℃.

7. The synthesis process of cefixime ring-opening side chain acid according to claim 1, characterized in that, The bromine and hydrogen peroxide are added over a period of 2 to 8 hours.

8. The synthesis process of cefixime ring-opening side chain acid according to claim 1, characterized in that, The bromination reaction and acid deprotection reaction also include a heat preservation reaction step, with a heat preservation reaction time of 1~6h.

9. The synthesis process of cefixime ring-opening side chain acid according to claim 1, characterized in that, The post-processing includes: direct cooling crystallization, filtration, and drying to obtain the product.

10. The synthesis process of cefixime ring-opening side chain acid according to claim 9, characterized in that, The cooling crystallization temperature is 0~20℃.

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