Preparation method of ceftazidime hydrochloride and intermediate thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of ceftazidime hydrochloride and an intermediate thereof. The preparation method comprises the following steps: by taking D-7-ACA as a raw material, salifying D-7-ACA with a sodium bicarbonate aqueous solution, and then reacting with pyridine under the action of a catalyst to obtain a 7-PYCA reaction solution; carrying out condensation reaction on the reaction liquid and ceftazidime active ester to obtain ceftazidime tert-butyl ester; and performing deprotection reaction on the obtained ceftazidime tert-butyl ester under the conditions of formic acid and hydrochloric acid, and finally crystallizing to obtain the ceftazidime hydrochloride. The method is low in cost, high in yield and purity, simple in process, less in three wastes and high in productivity, and has a very good industrialization value.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing ceftazidime hydrochloride and its intermediates. Background Technology

[0002] Ceftazidime is a third-generation cephalosporin antibiotic characterized by strong antibacterial activity, a broad antibacterial spectrum, and enzyme resistance. Discovered in 1978, it was first developed and marketed by GlaxoSmithKline in the UK in 1983. Ceftazidime was first marketed in China in 1992 and officially included in my country's Essential Medicines List in 1993. Ceftazidime exhibits broad-spectrum antibacterial activity against both Gram-positive and Gram-negative aerobic bacteria. Clinically, it is primarily used to treat infections caused by Gram-negative bacteria, as well as respiratory, urinary tract, gastrointestinal, biliary tract, and abdominal infections caused by susceptible bacteria, and severe infections such as sepsis, bacteremia, and peritonitis.

[0003] In recent years, the main methods for preparing ceftazidime hydrochloride include the following two:

[0004] 1. Synthetic route using GCLE as starting material

[0005]

[0006] This route begins with GCLE as the starting material, undergoing an iodination reaction with potassium iodide, followed by a substitution reaction with pyridine, deprotection by a phosphorus pentachloride and pyridine complex salt, and deprotection by phenol, resulting in 7-PYCA through four steps. 7-PYCA then undergoes a condensation reaction with an active ceftazidime ester under alkaline conditions, followed by hydrolysis under hydrochloric acid and formic acid conditions to obtain ceftazidime hydrochloride. This route requires four steps to obtain 7-PYCA, is lengthy, consumes a large amount of materials, and has poor atom economy.

[0007] 2. Synthetic route using 7-ACA as starting material

[0008]

[0009] This route uses 7-ACA as the starting material, employing HMDS for silanization protection, followed by iodination with trimethyliodosilane and then substitution with pyridine, yielding 7-APCA. 7-APCA undergoes a condensation reaction with the active ceftazidime ester under alkaline conditions, followed by hydrolysis under hydrochloric and formic acid conditions to obtain ceftazidime hydrochloride. This route is currently the mainstream synthetic route, and its process is shorter than the GCLE route. However, this route requires the use of expensive trimethyliodosilane, resulting in higher costs.

[0010] Therefore, it is necessary to develop a method with a short route, low cost, and high purity yield for the synthesis of ceftazidime hydrochloride. Summary of the Invention

[0011] To overcome the drawbacks of existing technologies, such as high cost and long processing steps, this invention uses D-7-ACA as a raw material, avoiding the expensive trimethyliodosilane, and employs a two-step process of condensation substitution and condensation. The new process features low reaction cost, fewer processing steps, and high yield, making it highly valuable for industrialization.

[0012] One of the objectives of this invention is to provide a one-pot method for preparing ceftazidime tert-butyl ester.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] A one-pot method for preparing ceftazidime tert-butyl ester includes the following steps:

[0015] S1: After D-7-ACA is salted with an aqueous sodium bicarbonate solution, it undergoes a substitution reaction with pyridine under the action of a catalyst to obtain a 7-PYCA reaction solution; the catalyst includes any one or more of sodium iodide, potassium iodide, lithium iodide, magnesium iodide, and calcium iodide; the molar ratio of D-7-ACA to the catalyst is 1:0.1~2.0;

[0016] S2: The 7-PYCA reaction solution obtained in S1 is condensed with ceftazidime active ester to obtain ceftazidime tert-butyl ester.

[0017] Preferably, the catalyst is any one or two of sodium iodide and potassium iodide, more preferably sodium iodide.

[0018] Preferably, the molar ratio of D-7-ACA to the catalyst is 1:0.3 to 1.0, more preferably 1:0.3 to 0.5, and even more preferably 1:0.3.

[0019] Preferably, the molar ratio of D-7-ACA to sodium bicarbonate is 1:1.0~3.0; the molar ratio of D-7-ACA to pyridine is 1:1.0~5.0; and the molar ratio of D-7-ACA to ceftazidime active ester is 1:0.5~3.0.

[0020] Preferably, the molar ratio of D-7-ACA to sodium bicarbonate is 1:1.0~1.5, more preferably 1:1.3.

[0021] Preferably, the molar ratio of D-7-ACA to pyridine is 1:2.0~2.5, more preferably 1:2.0.

[0022] Preferably, the molar ratio of D-7-ACA to the ceftazidime active ester is 1:0.9~1.5, more preferably 1:1.1.

[0023] Preferably, the reaction solvent for the substitution reaction and the condensation reaction is one or more mixed solvents selected from water, acetone, and acetonitrile.

[0024] More preferably, the reaction solvent for the substitution reaction is water.

[0025] More preferably, the reaction solvent for the condensation reaction is acetone or a mixture of water and acetone.

[0026] Preferably, the substitution reaction is carried out at a temperature of 40-80°C for 1-4 hours; the condensation reaction is carried out at a temperature of 10-40°C for 3-8 hours.

[0027] Preferably, the substitution reaction is carried out at a temperature of 50-70°C for 1.5-3 hours, and more preferably at 60°C for 2 hours.

[0028] Preferably, the condensation reaction is carried out at a temperature of 15-25°C for 4-6 hours, and more preferably at 20°C for 5 hours.

[0029] Preferably, the preparation of ceftazidime tert-butyl ester is carried out in a single reaction vessel.

[0030] As a preferred embodiment, in S1, after adding the catalyst and pyridine to the reaction system, nitrogen is used to purge once before the temperature is raised to react.

[0031] As a preferred option, a saturated sodium bicarbonate aqueous solution is used to adjust the pH during both the substitution and condensation reactions to ensure that the pH of the reaction system is 6.5~7.0.

[0032] As a preferred option, after the substitution reaction is complete, the temperature is lowered to 20°C, and the solution is decolorized with GA activated carbon and then filtered to obtain the 7-PYCA reaction solution.

[0033] As a preferred option, ceftazidime tert-butyl ester is obtained by crystallization after the condensation reaction is completed.

[0034] As a preferred method, acetone is used as the crystallization solvent.

[0035] As a preferred method, after the condensation reaction is completed, acetone is added to the reaction solution and hydrochloric acid is used to adjust the pH to 5.0~5.5; then the solution is kept at -5~5℃ for 3~6 hours to grow crystals; the solution is filtered and dried to obtain ceftazidime tert-butyl ester.

[0036] As a better option, the crystals are grown at 0°C for 4 hours.

[0037] The second objective of this invention is to provide a method for preparing ceftazidime hydrochloride.

[0038] To achieve the above objectives, the present invention adopts the following technical solution:

[0039] The preparation method of ceftazidime hydrochloride includes the following steps:

[0040] (1) Ceftazidime tert-butyl ester was prepared according to the aforementioned method;

[0041] (2) The ceftazidime tert-butyl ester obtained in step (1) is hydrolyzed with formic acid and hydrochloric acid, and ceftazidime hydrochloride is obtained by crystallization.

[0042] Preferably, the hydrolysis reaction is carried out at a temperature of 15-30°C for 0.5-3 hours, and more preferably at 20°C for 1 hour.

[0043] Preferably, the ratio of ceftazidime tert-butyl ester, hydrochloric acid, and formic acid is 1g:1~5ml:0.5~3ml, more preferably 1g:2ml:1ml.

[0044] As a preferred method, isopropanol is used as the crystallization solvent.

[0045] Preferably, the crystallization temperature is -10~0℃ and the crystal growth time is 2~5 hours, more preferably, the crystal growth time is -5℃ for 3 hours.

[0046] Preferably, the crystallization is specifically performed by adding isopropanol to the reaction solution obtained from hydrolysis, keeping it warm to grow crystals, filtering and drying to obtain ceftazidime hydrochloride.

[0047] The beneficial effects of this invention are as follows:

[0048] 1. This invention uses D-7-ACA as the starting material. D-7-ACA reacts with an aqueous sodium bicarbonate solution to form a salt, which then reacts with pyridine under a catalyst to obtain the intermediate 7-PYCA. The 7-PYCA reaction solution undergoes a condensation reaction with an active ceftazidime ester to obtain ceftazidime tert-butyl ester. Ceftazidime tert-butyl ester undergoes a deprotection reaction under formic acid and hydrochloric acid conditions, followed by crystallization to obtain ceftazidime hydrochloride. This method features inexpensive materials, fewer process steps, high product purity, high overall yield, good atom economy, low waste emissions, and is more suitable for industrial production.

[0049] 2. This invention uses D-7-ACA as a raw material, avoiding the expensive trimethyliodosilane, resulting in lower costs and higher economic value for industrial production.

[0050] 3. This invention uses a one-pot process to synthesize ceftazidime tert-butyl ester, and simultaneously performs two-step processes of condensation substitution and condensation, avoiding losses during the 7-PYCA crystallization process. After the condensation process, the total molar yield of ceftazidime tert-butyl ester is increased from 67.4% to about 80%. Attached Figure Description

[0051] Figure 1This is a schematic diagram of the synthetic reaction route for ceftazidime hydrochloride.

[0052] Figure 2 The HPLC chromatogram of the ceftazidime hydrochloride solid prepared in Example 1 is shown.

[0053] Figure 3 The HPLC chromatogram of the ceftazidime hydrochloride solid prepared in Example 2 is shown.

[0054] Figure 4 The HPLC chromatogram of the ceftazidime hydrochloride solid prepared in Example 6 is shown.

[0055] Figure 5 The HPLC chromatogram of the ceftazidime hydrochloride solid prepared in Example 7 is shown.

[0056] Figure 6 The ceftazidime hydrochloride solid prepared in Example 7 1 H-NMR spectrum.

[0057] Figure 7 The ceftazidime hydrochloride solid prepared in Example 7 13 C-NMR spectrum. Detailed Implementation

[0058] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0059] In this embodiment of the invention, the synthetic reaction route for ceftazidime hydrochloride is as follows: Figure 1 As shown in the figure, this invention uses D-7-ACA as the starting material. D-7-ACA reacts with an aqueous sodium bicarbonate solution to form a salt, which then reacts with pyridine under a catalyst to obtain the intermediate 7-PYCA. The 7-PYCA reaction solution undergoes a condensation reaction with an active ceftazidime ester to obtain ceftazidime tert-butyl ester. Ceftazidime tert-butyl ester undergoes a deprotection reaction under formic acid and hydrochloric acid conditions, followed by crystallization to obtain ceftazidime hydrochloride. This method features inexpensive materials, fewer process steps, high product purity, high overall yield, good atom economy, low waste emissions, and is more suitable for industrial production.

[0060] Information on each compound in this invention is shown in Table 1.

[0061] Table 1. Compound Information Table

[0062]

[0063] In this embodiment of the invention, the chromatographic conditions for HPLC detection are shown in Tables 2 and 3.

[0064] Table 2. Chromatographic conditions

[0065]

[0066] Table 3. Gradient elution program table

[0067]

[0068] Example 1. Preparation method of ceftazidime hydrochloride

[0069] (1) Preparation of 7-PYCA

[0070] Add D-7-ACA (100.0 g, 0.434 mol, 1.0 eq), water (250 ml), and sodium bicarbonate (47.4 g, 0.565 mol, 1.3 eq) to a three-necked flask and stir until dissolved. Add potassium iodide (72.1 g, 0.434 mol, 1.0 eq) and pyridine (68.7 g, 0.869 mol, 2.0 eq), purge once with nitrogen, and heat to 60°C and maintain the reaction temperature for 2 hours (adjust the pH using saturated sodium bicarbonate solution during the reaction to ensure the pH of the reaction system is 6.5~7.0).

[0071] After the reaction was complete, the temperature was lowered to 20°C, and 5.0 g of GA activated carbon was added for decolorization for 1 hour. After filtration, acetone (1000 ml) was added, and the pH was adjusted to 5.0-5.5 with hydrochloric acid. After pH adjustment, the mixture was kept at 0°C for crystal growth for 4 hours. After filtration and drying, 102.3 g of 7-PYCA was obtained, with a molar yield of 80.85%.

[0072] (2) Preparation of ceftazidime tert-butyl ester

[0073] Add 7-PYCA (100.0 g, 0.343 mol), ceftazidime active ester (180.7 g, 0.378 mol, 1.1 eq), water (250 ml), and acetone (250 ml) to a three-necked flask. After stirring and dispersing, add sodium bicarbonate (37.5 g, 0.446 mol, 1.3 eq) and incubate at 20°C for 5 hours (during the reaction, use saturated sodium bicarbonate aqueous solution to adjust the pH to ensure that the pH of the reaction system is 6.5~7.0).

[0074] After the reaction was complete, acetone (500 ml) was added, and the pH was adjusted to 5.0-5.5 with hydrochloric acid. After pH adjustment, the mixture was kept at 0°C for 4 hours to allow crystals to form. After filtration and drying, 172.5 g of ceftazidime tert-butyl ester was obtained, with a molar yield of 83.38%.

[0075] (3) Preparation of ceftazidime hydrochloride

[0076] Add ceftazidime tert-butyl ester (50.0 g, 0.083 mol, 1.0 eq), hydrochloric acid (100 ml), and formic acid (50 ml) to a three-necked flask, and incubate at 20°C for 1 hour.

[0077] After the reaction was complete, isopropanol (750 ml) was added dropwise to the reaction solution for crystallization, and the mixture was kept at -5°C for 3 hours. The crystals were then filtered and dried to obtain 48.8 g of ceftazidime hydrochloride with an HPLC purity of 99.95% and a molar yield of 94.95%. Its HPLC chromatogram is shown below. Figure 2 The integration results are shown in Table 4.

[0078] Table 4. Figure 2 Integral Results Table

[0079]

[0080] Example 2. Preparation method of ceftazidime hydrochloride

[0081] (1) Preparation of 7-PYCA

[0082] Add D-7-ACA (100.0 g, 0.434 mol, 1.0 eq), water (250 ml), and sodium bicarbonate (47.4 g, 0.565 mol, 1.3 eq) to a three-necked flask and stir until dissolved. Add potassium iodide (72.1 g, 0.434 mol, 1.0 eq) and pyridine (68.7 g, 0.869 mol, 2.0 eq), purge once with nitrogen, and heat to 60°C and maintain the reaction temperature for 2 hours (adjust the pH using saturated sodium bicarbonate solution during the reaction to ensure the pH of the reaction system is 6.5~7.0).

[0083] After the reaction was complete, the temperature was lowered to 20°C, and 5.0g of GA activated carbon was added for decolorization for 1 hour. The filtered 7-PYCA reaction solution was used for the next step of the reaction.

[0084] (2) Preparation of ceftazidime tert-butyl ester

[0085] In a three-necked flask, acetone (250 ml) and ceftazidime active ester (228.66 g, 0.478 mol, 1.1 eq) were added to the 7-PYCA reaction solution. The mixture was kept at 20 °C for 5 hours (the pH was adjusted using a saturated sodium bicarbonate aqueous solution during the reaction to ensure that the pH of the reaction system was 6.5~7.0).

[0086] After the reaction was complete, acetone (500 ml) was added, and the pH was adjusted to 5.0-5.5 with hydrochloric acid. After pH adjustment, the mixture was kept at 0°C for 4 hours to allow crystals to form. After filtration and drying, 209.8 g of ceftazidime tert-butyl ester was obtained, with a molar yield of 80.15%.

[0087] (3) Preparation of ceftazidime hydrochloride

[0088] Add ceftazidime tert-butyl ester (50.0 g, 0.083 mol, 1.0 eq), hydrochloric acid (100 ml), and formic acid (50 ml) to a three-necked flask, and incubate at 20°C for 1 hour.

[0089] After the reaction was complete, isopropanol (750 ml) was added dropwise to the reaction solution for crystallization, and the mixture was kept at -5°C for 3 hours. The crystals were then filtered and dried to obtain 48.1 g of ceftazidime hydrochloride, with an HPLC purity of 99.87% and a molar yield of 93.59%. The HPLC chromatogram is shown below. Figure 3 The integration results are shown in Table 5.

[0090] Table 5. Figure 3 Integral Results Table

[0091]

[0092] Example 3. Preparation method of ceftazidime hydrochloride

[0093] (1) Preparation of 7-PYCA

[0094] Add D-7-ACA (100.0 g, 0.434 mol, 1.0 eq), water (250 ml), and sodium bicarbonate (47.4 g, 0.565 mol, 1.3 eq) to a three-necked flask and stir until dissolved. Add potassium iodide (3.6 g, 0.022 mol, 0.05 eq) and pyridine (68.7 g, 0.869 mol, 2.0 eq), purge once with nitrogen, and heat to 60°C and maintain the reaction temperature for 8 hours (adjust the pH using saturated sodium bicarbonate solution during the reaction to ensure the pH of the reaction system is 6.5~7.0).

[0095] After the reaction was complete, the temperature was lowered to 20°C, and 5.0g of GA activated carbon was added for decolorization for 1 hour. The solution was dark in color after decolorization, so further processing was abandoned.

[0096] Example 4. Preparation method of ceftazidime hydrochloride

[0097] (1) Preparation of 7-PYCA

[0098] Add D-7-ACA (100.0 g, 0.434 mol, 1.0 eq), water (250 ml), and sodium bicarbonate (47.4 g, 0.565 mol, 1.3 eq) to a three-necked flask and stir until dissolved. Add potassium iodide (72.1 g, 0.434 mol, 1.0 eq) and pyridine (37.8 g, 0.478 mol, 1.1 eq), purge once with nitrogen, and heat to 60°C and maintain the reaction temperature for 6 hours (during the reaction, adjust the pH using a saturated sodium bicarbonate aqueous solution to ensure the pH of the reaction system is 6.5~7.0).

[0099] After the reaction was complete, the temperature was lowered to 20°C, and 5.0g of GA activated carbon was added for decolorization for 1 hour. The solution was darker after decolorization, so further processing was abandoned.

[0100] Example 5. Preparation method of ceftazidime hydrochloride

[0101] (1) Preparation of 7-PYCA

[0102] Add D-7-ACA (100.0 g, 0.434 mol, 1.0 eq), water (250 ml), and sodium bicarbonate (47.4 g, 0.565 mol, 1.3 eq) to a three-necked flask and stir until dissolved. Add potassium iodide (72.1 g, 0.434 mol, 1.0 eq) and pyridine (68.7 g, 0.869 mol, 2.0 eq), purge once with nitrogen, and heat to 80°C and maintain the reaction temperature for 2 hours (adjust the pH using a saturated sodium bicarbonate aqueous solution during the reaction to ensure the pH of the reaction system is 6.5~7.0).

[0103] After the reaction was complete, the temperature was lowered to 20°C, and 5.0g of GA activated carbon was added for decolorization for 1 hour. The solution was darker after decolorization, so further processing was abandoned.

[0104] Example 6. Preparation method of ceftazidime hydrochloride

[0105] (1) Preparation of 7-PYCA

[0106] Add D-7-ACA (100.0 g, 0.434 mol, 1.0 eq), water (250 ml), and sodium bicarbonate (47.4 g, 0.565 mol, 1.3 eq) to a three-necked flask and stir until dissolved. Add potassium iodide (21.6 g, 0.130 mol, 0.3 eq) and pyridine (68.7 g, 0.869 mol, 2.0 eq), purge once with nitrogen, and heat to 60°C and maintain the reaction temperature for 2 hours (adjust the pH using a saturated sodium bicarbonate aqueous solution during the reaction to ensure the pH of the reaction system is 6.5~7.0).

[0107] After the reaction was complete, the temperature was lowered to 20°C, and 5.0g of GA activated carbon was added for decolorization for 1 hour. The filtered 7-PYCA reaction solution was used for the next step of the reaction.

[0108] (2) Preparation of ceftazidime tert-butyl ester

[0109] In a three-necked flask, acetone (250 ml) and ceftazidime active ester (228.66 g, 0.478 mol, 1.1 eq) were added to the 7-PYCA reaction solution. The mixture was kept at 20 °C for 5 hours (the pH was adjusted using a saturated sodium bicarbonate aqueous solution during the reaction to ensure that the pH of the reaction system was 6.5~7.0).

[0110] After the reaction was complete, acetone (500 ml) was added, and the pH was adjusted to 5.0-5.5 with hydrochloric acid. After pH adjustment, the mixture was kept at 0°C for 4 hours to allow crystals to form. After filtration and drying, 208.7 g of ceftazidime tert-butyl ester was obtained, with a molar yield of 79.72%.

[0111] (3) Preparation of ceftazidime hydrochloride

[0112] Add ceftazidime tert-butyl ester (50.0 g, 0.083 mol, 1.0 eq), hydrochloric acid (100 ml), and formic acid (50 ml) to a three-necked flask, and incubate at 20°C for 1 hour.

[0113] After the reaction was complete, isopropanol (750 ml) was added dropwise to the reaction solution for crystallization, and the mixture was kept at -5°C for 3 hours. The crystals were then filtered and dried to obtain 48.7 g of ceftazidime hydrochloride, with an HPLC purity of 99.86% and a molar yield of 94.75%. The HPLC chromatogram is shown below. Figure 4 The integration results are shown in Table 6.

[0114] Table 6. Figure 4 Integral Results Table

[0115]

[0116] Example 7. Preparation method of ceftazidime hydrochloride

[0117] (1) Preparation of 7-PYCA

[0118] Add D-7-ACA (100.0 g, 0.434 mol, 1.0 eq), water (250 ml), and sodium bicarbonate (47.4 g, 0.565 mol, 1.3 eq) to a three-necked flask and stir until dissolved. Add sodium iodide (19.5 g, 0.130 mol, 0.3 eq) and pyridine (68.7 g, 0.869 mol, 2.0 eq), purge once with nitrogen, and heat to 60°C and maintain the temperature for 2 hours (adjust the pH using a saturated sodium bicarbonate solution during the reaction to ensure the pH of the reaction system is 6.5~7.0).

[0119] After the reaction was complete, the temperature was lowered to 20°C, and 5.0g of GA activated carbon was added for decolorization for 1 hour. The filtered 7-PYCA reaction solution was used for the next step of the reaction.

[0120] (2) Preparation of ceftazidime tert-butyl ester

[0121] In a three-necked flask, acetone (250 ml) and ceftazidime active ester (228.66 g, 0.478 mol, 1.1 eq) were added to the 7-PYCA reaction solution. The mixture was kept at 20 °C for 5 hours (the pH was adjusted using a saturated sodium bicarbonate aqueous solution during the reaction to ensure that the pH of the reaction system was 6.5~7.0).

[0122] After the reaction was complete, acetone (500 ml) was added, and the pH was adjusted to 5.0-5.5 with hydrochloric acid. After pH adjustment, the mixture was kept at 0°C for 4 hours to allow crystals to form. After filtration and drying, 209.1 g of ceftazidime tert-butyl ester was obtained, with a molar yield of 79.88%.

[0123] (3) Preparation of ceftazidime hydrochloride

[0124] Add ceftazidime tert-butyl ester (50.0 g, 0.083 mol, 1.0 eq), hydrochloric acid (100 ml), and formic acid (50 ml) to a three-necked flask, and incubate at 20°C for 1 hour.

[0125] After the reaction was complete, isopropanol (750 ml) was added dropwise to the reaction solution for crystallization, and the crystals were kept at -5°C for 3 hours. After filtration and drying, 48.3 g of ceftazidime hydrochloride was obtained, with an HPLC purity of 99.87% and a molar yield of 93.98%. The HPLC results of the obtained ceftazidime hydrochloride solid are as follows. Figure 5 As shown, the integration results are shown in Table 7; 1 H-NMR spectrum as follows Figure 6 As shown; 13 C-NMR spectra as follows Figure 7 As shown.

[0126] Table 7. Figure 5 Integral Results Table

[0127]

[0128] The experimental results of Examples 1-7 are analyzed and discussed:

[0129] 1. Example 2 was a one-pot process of condensation compared to Example 1, which eliminated the loss during the 7-PYCA crystallization process. After the condensation process, the total molar yield of ceftazidime tert-butyl ester increased from 67.4% to 80.15%.

[0130] 2. In Example 3, the amount of catalyst was reduced to 0.05 eq, which required extending the reaction time. The reaction solution was dark in color before and after decolorization, so the crystallization process was abandoned.

[0131] 3. In Example 4, the catalyst equivalent was kept constant, but the amount of pyridine was reduced, which prolonged the reaction time and caused the same problem as in Example 3.

[0132] 4. In Example 5, the reaction temperature was increased to 80°C. During the reaction, a large amount of dark-colored pigment was degraded, resulting in the same problem as in Example 3.

[0133] 5. In Example 6, the amount of catalyst was reduced to 0.3 eq, and the reaction effect was comparable to that of Example 2 with 1.0 eq potassium iodide.

[0134] 6. Comparing Examples 6 and 7, the reaction effects of 0.3 eq of potassium iodide and sodium iodide are comparable. Although the unit price per kilogram of potassium iodide and sodium iodide is not significantly different, sodium iodide is cheaper when converted to yuan / mol. Therefore, the production scheme of Example 7 has a lower production cost than that of Example 6.

[0135] In summary, the production schemes of Examples 2, 6, and 7 all performed well, with Example 7 showing the best economic performance. This process features high yield, low cost, simple procedures, minimal waste, and high capacity, and has significant industrialization value.

Claims

1. A method for preparing ceftazidime tert-butyl ester in a one-pot process, characterized in that, Includes the following steps: S1: After D-7-ACA is salted with an aqueous sodium bicarbonate solution, it undergoes a substitution reaction with pyridine under the action of a catalyst to obtain a 7-PYCA reaction solution; the catalyst includes any one or more of sodium iodide, potassium iodide, lithium iodide, magnesium iodide, and calcium iodide; the molar ratio of D-7-ACA to the catalyst is 1:0.1~2.0; S2: The 7-PYCA reaction solution obtained in S1 is condensed with ceftazidime active ester to obtain ceftazidime tert-butyl ester.

2. The method according to claim 1, characterized in that, The catalyst is sodium iodide.

3. The method according to claim 1, characterized in that, The molar ratio of D-7-ACA to the catalyst is 0.3 to 0.

5.

4. The method according to claim 1, characterized in that, The molar ratio of D-7-ACA to sodium bicarbonate is 1:1.0~3.0; the molar ratio of D-7-ACA to pyridine is 1:1.0~5.0; and the molar ratio of D-7-ACA to ceftazidime active ester is 1:0.5~3.

0.

5. The method according to claim 1, characterized in that, The reaction solvents for the substitution reaction and the condensation reaction are one or more mixed solvents selected from water, acetone, and acetonitrile.

6. The method according to claim 1, characterized in that, The substitution reaction is carried out at a temperature of 40-80°C for 1-4 hours; the condensation reaction is carried out at a temperature of 10-40°C for 3-8 hours.

7. The method according to claim 1, characterized in that, During both the substitution and condensation reactions, a saturated sodium bicarbonate aqueous solution was used to adjust the pH to ensure that the pH of the reaction system was 6.5-7.

0.

8. A method for preparing ceftazidime hydrochloride, characterized in that, Includes the following steps: (1) Ceftazidime tert-butyl ester is prepared according to the method of any one of claims 1 to 7; (2) The ceftazidime tert-butyl ester obtained in step (1) is hydrolyzed with formic acid and hydrochloric acid, and ceftazidime hydrochloride is obtained by crystallization.

9. The method according to claim 8, characterized in that, The hydrolysis reaction is carried out at a temperature of 15-30°C for 0.5-3 hours.

10. The method according to claim 8, characterized in that, The crystallization solvent is isopropanol.

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