A crystalline form a of a cephalosporin nucleus iodide monohydrate and a method for preparing the same

Abstract

The application discloses a crystal form A of a cephem iodide monohydrate compound and a preparation method thereof. The crystal form A contains the following characteristic peaks in X-ray powder diffraction spectrum: 9.7+ / -0.2°, 11.9+ / -0.2°, 13.5+ / -0.2°, 14.3+ / -0.2°, 17.9+ / -0.2°, 18.6+ / -0.2°, 19.9+ / -0.2°, 20.4+ / -0.2°, 23.2+ / -0.2°, 24.1+ / -0.2°, 24.8+ / -0.2°, 26.2+ / -0.2°, 30.3+ / -0.2°, 30.5+ / -0.2° and 34.8+ / -0.2°. The application further discloses a preparation method of the crystal form A. The crystal form A obtained according to the preparation method has good stability, high purity, meets the needs of drug production, and the raw material used in the preparation method is cheap and easy to obtain, and has high yield and purity.

Description

Technical Field

[0001] This invention relates to the field of chemical raw material technology, and in particular to a crystal form A of 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate and its preparation method, belonging to the field of chemical drug intermediates. Background Technology

[0002] Ceftazidime is a semi-synthetic third-generation cephalosporin. Similar to other third-generation cephalosporins, it has a broad range of activity against Gram-positive and Gram-negative bacteria. However, unlike other cephalosporins, it is effective against Pseudomonas aeruginosa but has weaker resistance to Gram-positive bacteria.

[0003] In the synthesis of ceftazidime, 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate (7-PYCA) and the active ester of the ceftazidime side chain (TEAM) are key materials. Zheng Yulin disclosed a method for synthesizing ceftazidime (Improved Synthetic Process of Ceftazidime, Chinese Journal of Medicinal Chemistry, 2010, 20(03), pp. 198-200). In this method, the intermediate 7-ACA and hexamethyldisilazane are refluxed in dichloromethane for 8 hours. Then, trimethyliodosilane is used as an iodination reagent to perform a 3-position substitution reaction, which is quenched with hydrochloric acid. The pH is adjusted with acetone and triethylamine to crystallize and obtain the corresponding 7-amino-3-(1-pyridinemethyl)cephalosporin hydrochloride (7-APCA) with a yield of 83.2%.

[0004] Meng Jiao and Wu Jingjing disclosed a method for synthesizing ceftazidime (Improved Synthesis Process of Ceftazidime, Science and Technology Forum, 2012, 07, p. 37). In this method, intermediate 7-ACA and hexamethyldisilazane are refluxed in dichloromethane for 10 h. Then, trimethyliodosilane is used as an iodination reagent to perform a 3-position substitution reaction, which is quenched with hydrochloric acid. The mixture is passed through a macroporous resin, and the pH is adjusted with acetone and triethylamine to crystallize and obtain the corresponding 7-amino-3-(1-pyridinemethyl)cephalosporin hydrochloride (7-APCA).

[0005] US Patent 4540779A mentions a crystallization method for 7-amino-3-(1-pyridinemethyl)cephalosporin monohydrochloride monohydrate, but the patent mentions that the intermediate monohydrochloride monohydrate is obtained by recrystallization of 7-amino-3-(1-pyridinemethyl)cephalosporin dihydrochloride dihydrate in a mixed solvent of methanol, ethanol, acetone and water, respectively, resulting in a large loss in product yield.

[0006] Liu Yuting et al. reported a method for synthesizing 7-amino-3-(1-pyridinemethyl)cephalosporin (7-APCA) halides (Synthetic route of 7-amino-3-(1-pyridinemethyl)cephalosporin (7-APCA) halides [J]. Heilongjiang Medicine, 2004, 17(5): 359-362). The article mentioned that the hydroiodide intermediate of ceftazidime was obtained by directly adding ethanol or methanol to the reaction solution after substitution to deprotect the product. However, this process had a low yield and the product purity was only 72% to 80%, so it could not be used for the next step of the reaction.

[0007] CN201110396595.3 reports a method for preparing the hydrohalate of ceftazidime intermediate (6R,7R)-7-amino-3-pyridinemethyl-ceftazidime-3-ene-4-carboxylic acid by using 7-aminocephalosporanic acid as a raw material, followed by silanization, iodination, and reaction with pyridine. The product is then added to an oxidizing agent, hydrochloric acid, or a mixed solvent of organic solvent and water to obtain the hydrohalate. This invention yields a yellow product with HPLC >98%, an effective content of 63.3%–65%, and a yield of 90.3%–91%. However, this process results in a product with high absorbance but relatively low effective content and poor product stability.

[0008] Most of the literature reports mentioned above are mainly about the preparation of 7-amino-3-(1-pyridinemethyl)cephalosporin hydrochloride (7-APCA), and no direct preparation technology for 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate is provided. Moreover, the yield and purity are generally not high. In view of the shortcomings of the above-mentioned existing technologies, this invention proposes a method for synthesizing a ceftazidime intermediate (compound of structural formula 1) suitable for industrial production. Summary of the Invention

[0009] The purpose of this invention is to provide a crystalline form A of 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate and its preparation method. Crystal form A exhibits good stability, and the preparation method utilizes inexpensive and readily available raw materials, resulting in high yield and product purity.

[0010] A crystalline form A of 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate contains the following characteristic peaks measured by 2θ reflection angles in its X-ray powder diffraction pattern: 9.7±0.2°, 11.9±0.2°, 13.5±0.2°, 14.3±0.2°, 17.9±0.2°, 18.6±0.2°, 19.9±0.2°, 20.4±0.2°, 23.2±0.2°, 24.1±0.2°, 24.8±0.2°, 26.2±0.2°, 30.3±0.2°, 30.5±0.2°, and 34.8±0.2°.

[0011] The chemical structural formula 1 of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate is shown below:

[0012]

[0013] This invention also provides a method for preparing crystal form A of 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate, comprising the following steps:

[0014] (A) Add hexamethyldisilane and iodine to a chlorinated alkane solvent to obtain an iodosilylating reagent;

[0015] (B) 7-ACA and hexamethyldisilazane are amino protected under the catalysis of imidazole hydroiodide, and then the iodosilylating reagent solution obtained in step (A) is added to carry out silanization reaction, followed by the addition of pyridine to carry out substitution reaction, to obtain a mixture of 7-amino-3-(1-pyridinemethyl)cephalosporin iodide and hydrogen chloride.

[0016] (C) After dissolving the mixture of 7-amino-3-(1-pyridinemethyl)cephalosporin iodide and hydrogen chloride obtained in step (B), an iodine salt replacement agent is added for replacement, and after post-treatment, the crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodate monohydrate is obtained.

[0017] The preparation reaction steps of this invention are as follows:

[0018] (A)

[0019]

[0020] (B)

[0021]

[0022] (C)

[0023]

[0024] Preferably, in step (A) preparation of the iodosilane reagent, the chloroalkane solvent is dichloromethane or chloroform;

[0025] The temperature for preparing the silicifying reagent solution is 0–25°C, preferably 18–22°C;

[0026] The weight ratio of hexamethyldisilane to iodine is 1:1.70 to 1.75.

[0027] Preferably, in step (B), the amount of imidazole hydroiodide is 0.04 to 0.01 times the weight of 7-ACA;

[0028] The amino protection temperature is 45℃~50℃, and the reaction time is 4~5h. The addition of imidazole hydroiodate can effectively shorten the reaction time and improve the yield; if imidazole hydroiodate is not present as a catalyst, the silanization protection reaction time increases significantly and may reduce the product yield.

[0029] Preferably, in step (B), the solvent used for the silanization reaction is a chloroalkane solvent, including dichloromethane or chloroform, and the amount of solvent used is 3 to 4 times the weight of 7-ACA.

[0030] In step (B), the mass ratio of trimethylchlorosilane to 7-ACA is 0.1 to 0.2:1, and its main function is to remove residual ammonia.

[0031] The mass ratio of N,N-diethylaniline to 7-ACA is 0.6 to 0.8:1.

[0032] Preferably, in step (B), the post-processing includes: cooling, then adding a quenching agent for quenching, adding a diluent after quenching, and filtering to obtain the mixture of 7-amino-3-(1-pyridinemethyl)cephalosporin iodide and hydrogen chloride.

[0033] Preferably, the quenching agent is an aqueous solution of 45% to 50% acetone, and the amount of quenching agent is 1 to 3 times the weight of 7-ACA; the quenching temperature is -25℃ to 15℃.

[0034] Preferably, the diluent is acetone or methanol, and the amount of diluent used is 10 to 15 times the weight of 7-ACA; the quenching reaction temperature is -25℃ to 15℃.

[0035] Preferably, in step (C), hydrochloric acid or hydroiodic acid aqueous solution is used as the dissolving solution for dissolution;

[0036] The dissolution temperature is -5 to 15℃, preferably 3℃.

[0037] Preferably, in step (C), the iodine salt replacement agent is potassium iodide, sodium iodide, or lithium iodide, preferably sodium iodide.

[0038] In step (C), after the reaction is complete, neutralization is performed with a base, followed by recrystallization to obtain crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate. Preferably, the base is NaOH, triethylamine, or potassium carbonate.

[0039] The recrystallization is performed at a pH of 2.8–3.0 and a crystallization temperature of 0–15°C.

[0040] Furthermore, the 7-amino-3-(1-pyridinemethyl)cephalosporin iodine monohydrate crystal form A obtained by the preparation method of the present invention has an iodine content ≥26%, a chlorine content ≤3%, and a moisture content ≤6%, which meets the quality standard requirements.

[0041] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0042] The 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate obtained by the method of the present invention has good crystal form A stability and high purity, which meets the needs of drug production. Moreover, the raw materials used in the preparation method are inexpensive and readily available, and the product yield is high. Attached Figure Description

[0043] Figure 1 HPLC purity chromatogram of solid form A of 7-amino-3-(1-pyridinemethyl)cephalosporin iodine monohydrate prepared in Example 1;

[0044] Figure 2 The X-ray diffraction pattern of crystal form A of 7-amino-3-(1-pyridinemethyl)cephalosporin iodine monohydrate in Example 2 is shown. Detailed Implementation

[0045] The following examples illustrate specific embodiments of the present invention and are intended to explain the invention, but not to limit it in any way.

[0046] Example 1

[0047] Add 300g of dichloromethane and 92g of iodine to a clean 500mL reaction flask. Under nitrogen protection, slowly add 53g of hexamethyldisilane, keeping the temperature between 18 and 22°C. After the addition is complete, continue stirring until the solid iodine dissolves and the temperature drops to 0°C for later use (part A).

[0048] In a clean 3000mL reaction flask, add 150.0g 7-ACA, 450.0g dichloromethane, and 0.6g imidazole hydroiodate. Stir and heat to reflux. Slowly add 116.0g hexamethyldisilazane, and reflux at 45-50℃ for 4-5 hours. No ammonia gas is emitted. Cool to 5-10℃, add 17.0g trimethylchlorosilane and 100.0g N,N-diethylaniline, stir for 5 minutes, add 345.0g of the pre-prepared part A, and react at 13-15℃ for 4 hours. Take a sample and test for 7-ACA residue (less than 1.5mg / ml). Cool again, and after the temperature drops below 0℃, add 84.0g pyridine. Heat to 13-15℃ and react for 1.5 hours. Take a sample and test for iodinated residue (<1.5%). Add 0.8g of sodium metabisulfite. After the addition is complete, lower the temperature to -15℃, and slowly add a pre-cooled quenching agent (120.0g of acetone and 120.0g of water) at a temperature below -25℃ to -15℃. A coffee-colored solid precipitates out. After stirring the reaction for 10 minutes, add 2250g of acetone diluent dropwise. After the addition is complete, filter the solution. Wash the filter cake with 100g of ice water at 0-2℃ to obtain 291g of a brown wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride.

[0049] 291g of the wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride obtained in the previous step was added to a 2000mL reaction flask, along with 510.0g of purified water and 150.0g of methanol. The mixture was stirred and kept at -5℃. Approximately 110.0g of 36% hydrochloric acid was added dropwise. After the solid dissolved completely, 3.0g of pharmaceutical-grade 767 activated carbon and 15g of sodium metabisulfite were added. The mixture was stirred and decolorized for 30min. The mixture was filtered, and the filtrate was collected and 50g of sodium iodide was added to react for 1h. After the reaction was complete, the pH was adjusted to 2.8-3.0 with approximately 20% NaOH at 5-10℃ to precipitate the product. After crystallization for 1h, the product was filtered and washed with 200g of 5% acetone. The product was dried under vacuum to obtain the wet product, which was then placed in a vacuum oven at T=30℃ and a vacuum degree of -0.08MPa or higher for 2-3h. 214.4 g of off-white 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate (PYCA) was obtained (yield 89.1%, HPLC = 99.28%, see [reference needed]). Figure 1 HACA lactone = 0.13%, 7-ACA = 0.05%, pyridine = 0.04%, other unknown total impurities 0.50%, iodine content 27.34%, chlorine content 0.14%, absorbance 0.012, moisture 4.51%; effective content 68.0%.

[0050] Example 2

[0051] Add 350g chloroform and 94g iodine to a clean 500mL reaction flask, under nitrogen protection, slowly add 53.7g hexamethyldisilane, keeping the temperature between 10 and 15°C. After the addition is complete, continue stirring until the solid iodine dissolves completely and the mixture is cooled to 0°C for later use (part B).

[0052] Add 150.0g 7-ACA, 600.0g chloroform, and 1.5g imidazole hydroiodate to a clean 3000mL reaction flask. Stir and heat to 55℃, then slowly add 120.0g hexamethyldisilazane. Control the internal temperature at 45-50℃ and react for 4-5 hours. Cool down to 5-10℃, add 16.0g trimethylchlorosilane and 105.0g N,N-diethylaniline, stir for 5 minutes, then add 497.7g of the pre-prepared B component. Control the temperature at 10-15℃ and react for 4-5 hours. Take a sample and test for 7-ACA residue (less than 1.0mg / ml). If the result is acceptable, cool down again. After the temperature drops below 0℃, add 90.0g pyridine and heat to 13-15℃ and react for 1.5 hours. Take a sample and test for iodine residue (<1.5%). If the result is acceptable, the result is acceptable. Add 0.8g of sodium metabisulfite. After the addition is complete, lower the temperature to -25℃. Slowly add a pre-cooled quencher mixture (150.0g acetone and 180.0g water) at a temperature below -25℃ to -15℃, causing a coffee-colored solid to precipitate. Stir the reaction for 10 minutes, then add 1500g of methanol diluent dropwise. After the addition is complete, filter the mixture. Wash the filter cake with 120g of ice water at 0-2℃ to obtain 277g of a brown wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride.

[0053] The 277 wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride obtained in the previous step was added to a 2000 ml reaction flask. 600.0 g of purified water and 150.0 g of methanol were added, and the mixture was stirred and heated to 3℃. 36% hydrochloric acid was added until the solution was clear. 3.0 g of pharmaceutical-grade 767 activated carbon and 10 g of sodium metabisulfite were added, and the mixture was stirred for decolorization for 30 min. The mixture was filtered, and the filtrate was collected and 40 g of potassium iodide was added to react for 1 h. After the reaction, the pH was adjusted to 2.8–3.0 with potassium carbonate aqueous solution at 0–5℃ to precipitate the product. After crystallization for 1 h, the product was filtered and washed with 200 g of acetone containing 5% water. The product was dried under vacuum to obtain 7-PYCA wet product, which was then placed in a vacuum oven at T = 30℃ and a vacuum degree of -0.08 MPa or higher for 2–3 h. 200.2 g of off-white 7-PYCA dry product was obtained. (Yield 83.2%, HPLC = 99.0%, HACA lactone = 0.4%; 7-ACA = 0.09%, pyridine = 0.04%, other unknown total impurities 0.47%, iodine content 28.1%, chlorine content 0.12%, absorbance 0.012, moisture 4.47%, effective content 67.2%).

[0054] The solid obtained in Example 2 was subjected to powder X-ray diffraction.

[0055] Measurement instrument: Rigaku X-ray powder diffractometer (Japan)

[0056] Measurement conditions:

[0057] X-Ray generator 40kV, 15mA Scan 1D (Scan) Incident primary No unit Scan speed / Duration 10.00° / min Goniometer MiniFlex 300 / 600 Step width 0.01° Attachment ASC-8 Scan axis θ / 2θ Detector D / teX Ultra2 Scan range 3～50° IHS 10mm DS 1.25deg SS 8.0mm

[0058] In X-ray powder diffraction patterns ( Figure 2 The characteristic peaks of the 2θ reflection angle measured in the figure are: 9.7±0.2°, 11.9±0.2°, 13.5±0.2°, 14.3±0.2°, 17.9±0.2°, 18.6±0.2°, 19.9±0.2°, 20.4±0.2°, 23.2±0.2°, 24.1±0.2°, 24.8±0.2°, 26.2±0.2°, 30.3±0.2°, 30.5±0.2°, and 34.8±0.2°.

[0059] The specific data is shown in the table below:

[0060]

[0061] Example 3

[0062] Add 400g chloroform and 94g iodine to a clean 500ml reaction flask, under nitrogen protection, slowly add 53g hexamethyldisilane, keeping the temperature between 10 and 15°C. After the addition is complete, continue stirring until the solid iodine dissolves completely. Cool to 0°C for later use (part C).

[0063] Add 150.0g 7-ACA, 500.0g dichloromethane, and 1.0g imidazole hydroiodate to a clean 3000mL reaction flask. Stir and heat to 50℃, then slowly add 124.0g hexamethyldisilazane. Control the internal temperature at 45-50℃ and react for 4-5 hours. Cool down to 5-10℃, add 18.0g trimethylchlorosilane and 116.0g N,N-diethylaniline, stir for 5 minutes, then add the pre-prepared 547g C sample. Control the temperature at 10-15℃ and react for 4-5 hours. Take a sample and test for 7-ACA residue (less than 1.0mg / ml). If the residue is qualified, cool down again. After the temperature drops below 0℃, add 90.0g pyridine and heat to 13-15℃ and react for 1.5 hours. Take a sample and test for iodine residue (<1.5%). If the residue is qualified, the residue is qualified. Add 1.0g of sodium metabisulfite. After the addition is complete, lower the temperature to -25℃ and slowly add a pre-cooled quencher mixture (150.0g acetone and 150.0g water) at -25℃, causing a coffee-colored solid to precipitate. After stirring the reaction for 10 minutes, add 2000g of acetone diluent dropwise. After the addition is complete, filter the mixture. Wash the filter cake with 120g of ice water at 0-2℃ to obtain 289g of a brown wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride.

[0064] The wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride obtained in the previous step was added to a 2000 ml reaction flask. 550.0 g of purified water and 150.0 g of methanol were added, and the mixture was stirred and the temperature controlled at 15–20 °C. 45% hydroiodic acid was added dropwise until the solid dissolved. 4.0 g of pharmaceutical-grade 767 activated carbon and 10 g of sodium metabisulfite were added, and the mixture was stirred for decolorization for 30 min. The mixture was filtered, and 10 g of sodium iodide was added back to the filtrate. The pH was adjusted to 2.8–3.0 with triethylamine at 10–15 °C. 2000 g of acetone was added dropwise, and the mixture was filtered, washed, and the filter cake was washed with 100 g of cold water at 0 °C. The mixture was then dried under vacuum to obtain wet 7-PYCA. The dried product was placed in a vacuum oven at T = 30 °C and a vacuum degree of -0.08 MPa or higher for 2–3 h. 221.1 g of pale yellow dried 7-PYCA was obtained. (Yield 91.8%, HPLC = 99.20%, HACA lactone = 0.35%, 7-ACA = 0.10%, pyridine = 0.04%, other unknown total impurities 0.34%, iodine content 28.3%, chlorine content 0.10%, absorbance 0.023, moisture 4.8%, effective content 67.2%).

[0065] Preparation in Example 4 (Reference CN201110396595.3)

[0066] 30g (0.11mol) of 7-ACA, 300ml of dichloromethane, and 60ml (0.24mol) of N,O-bis(trimethylsilylacetamide) (BSA) were placed in a reaction flask and reacted at 20-25°C for 2 hours. Then, 16.2ml (0.16mol) of cyclohexene and 32g (0.16mol) of trimethylsilyl iodide were added under ice bath conditions, and the reaction was continued at room temperature for 3 hours. Finally, 18ml (0.22mol) of pyridine was added under ice bath conditions, and the reaction was continued for another 1 hour. The resulting solution was then transferred to a container at room temperature. The reactant liquid was added dropwise to a mixed solvent of 800 ml methanol and 100 ml water. After the addition was complete, the mixture was stirred for 1 hour, filtered, and the filter cake was washed with 100 ml methanol and dried under vacuum to obtain 45.7 g of yellow 7-PYCA (HPLC = 98.1%, 7-ACA = 0.56%, HACA lactone = 0.50%, other unknown total impurities 0.72%), with a water content of 4.4%, iodide ion content of 29.0%, absorbance of 0.27, and effective content of 63.4%.

[0067] Example 5

[0068] Add 300g of dichloromethane and 92g of iodine to a clean 500ml reaction flask. Under nitrogen protection, slowly add 53g of hexamethyldisilane, keeping the temperature between 18 and 22°C. After the addition is complete, continue stirring until the solid iodine dissolves and the temperature drops to 0°C for later use (part A).

[0069] Add 150.0 g 7-ACA and 650.0 g dichloromethane to a clean 3000 mL reaction flask, stir and heat to reflux, then slowly add 116.0 g hexamethyldisilazane, reflux at 45-50 °C for 10-12 h until no ammonia gas is released. Cool to 5-10 °C, add 17.0 g trimethylchlorosilane and 100.0 g N,N-diethylaniline, stir for 5 minutes, then add 345.0 g of the pre-prepared part A, and react at 13-15 °C for 4 h. Take a sample and test for 7-ACA residue (less than 1.5 mg / mL). Cool again, and after the temperature drops below 0 °C, add 84.0 g pyridine, heat to 13-15 °C and react for 1.5 h. Take a sample and test for iodine residue (<1.5%). Add 0.8g of sodium metabisulfite. After the addition is complete, lower the temperature to -15℃, and slowly add a pre-cooled quenching agent (120.0g of acetone and 120.0g of water) at a temperature below -25℃ to -15℃. A coffee-colored solid precipitates out. After stirring the reaction for 10 minutes, add 2250g of acetone diluent dropwise. After the addition is complete, filter the solution. Wash the filter cake with 100g of ice water at 0-2℃ to obtain 291g of a brown wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride.

[0070] The wet mixture of 7-amino-3-(1-pyridylmethyl)cephalosporin iodide and hydrogen chloride obtained in the previous step (291 g) was added to a 2000 ml reaction flask. 510.0 g of purified water and 150.0 g of methanol were added, and the mixture was stirred and kept at -5°C. Approximately 110.0 g of 36% hydrochloric acid was added dropwise. After the solid dissolved, 3.0 g of pharmaceutical-grade 767 activated carbon and 15 g of sodium metabisulfite were added, and the mixture was stirred for decolorization for 30 min. The mixture was filtered, and the filtrate was collected and 50 g of sodium iodide was added to react for 1 h. After the reaction was complete, the pH was adjusted to 2.8–3.0 with approximately 20% NaOH at 5–10°C to precipitate the product. After crystallization for 1 h, the product was filtered and washed with 200 g of 5% acetone. The product was dried under vacuum to obtain the wet product, which was then placed in a vacuum oven at T = 30°C and a vacuum degree of -0.08 MPa or higher for 2–3 h. 188.1 g of yellowish-brown 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate (PYCA) was obtained. (Yield 78.1%, HPLC = 99.01%, HACA lactone = 0.13%, 7-ACA = 0.25%, pyridine = 0.03%, other unknown total impurities 0.61%, iodine content 27.41%, chlorine content 0.15%, absorbance 0.035, water 4.57%; effective content 68.0%).

[0071] Example 6

[0072] Accelerated testing was conducted on the products of Examples 1 and 4, with a comparative test performed at 50°C for 5 days: (1g of sample was placed in a 20ml vial and sealed with a rubber stopper). The results are shown in the table below.

[0073]

[0074] The above experimental results show that the content of crystal form A obtained in Example 1 of the present invention did not decrease significantly after five days of acceleration, while the content of the product obtained in Example 4 according to the prior art decreased significantly, indicating that the stability of crystal form A obtained by the present invention is higher.

Claims

1. A method for preparing crystal form A of 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate, characterized in that, Includes the following steps: (A) Add hexamethyldisilane and iodine to a chlorinated alkane solvent to obtain an iodosilylating reagent solution; (B) 7-ACA and hexamethyldisilazane are amino-protected under the catalysis of imidazole hydroiodide, and then trimethylchlorosilane, N,N-diethylaniline and the iodosilylating reagent solution obtained in step (A) are added to carry out the iodination reaction, followed by the addition of pyridine to carry out the substitution reaction. After the reaction is completed, a mixture of 7-amino-3-(1-pyridinemethyl)cephalosporin iodide and hydrogen chloride is obtained after post-treatment. (C) After dissolving the mixture of 7-amino-3-(1-pyridinemethyl)cephalosporin iodide and hydrogen chloride obtained in step (B), an iodine salt replacement agent is added for replacement, and after post-treatment, the crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodate monohydrate is obtained. In step (B), the amount of imidazole hydroiodide is 0.01 times the weight of 7-ACA; The amino protection temperature is 45℃~50℃, and the reaction time is 4~5h; In step (C), after the reaction is complete, the mixture is neutralized with an alkali and then recrystallized to obtain crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate. The recrystallization occurs at a pH of 2.8 to 3.0 and a crystallization temperature of 0 to 15°C. The crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate contains the following characteristic peaks measured by 2θ reflection angles in its X-ray powder diffraction pattern: 9.7±0.2°, 11.9±0.2°, 13.5±0.2°, 14.3±0.2°, 17.9±0.2°, 18.6±0.2°, 19.9±0.2°, 20.4±0.2°, 23.2±0.2°, 24.1±0.2°, 24.8±0.2°, 26.2±0.2°, 30.3±0.2°, 30.5±0.2°, and 34.8±0.2°. The structure of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate is shown in the following formula: 。 2. The method for preparing crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A is shown in Figure 2.

3. The method for preparing crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate according to claim 1, characterized in that, In step (A), the chloroalkane solvent is dichloromethane or chloroform; The temperature for preparing the iodosilylating reagent solution is 0~25℃; The weight ratio of hexamethyldisilane to iodine is 1:1.70~1.7.

5.

4. The method for preparing crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate according to claim 1, characterized in that, In step (B), the solvent used for the iodination reaction is dichloromethane or chloroform, and the amount of solvent used is 3 to 4 times the weight of 7-ACA.

5. The method for preparing crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate according to claim 1, characterized in that, In step (B), the post-processing includes: cooling, then adding a quenching agent for quenching, adding a diluent after quenching, and filtering to obtain the mixture of 7-amino-3-(1-pyridinemethyl)cephalosporin iodide and hydrogen chloride.

6. The method for preparing crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate according to claim 5, characterized in that, The quenching agent is an aqueous solution of 45%~50% acetone, and the amount of quenching agent used is 1~3 times the weight of 7-ACA; the quenching temperature is -25℃~15℃.

7. The method for preparing crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate according to claim 5, characterized in that, The diluent is acetone or methanol, and the amount of diluent used is 10 to 15 times the weight of 7-ACA; the quenching reaction temperature is -25℃ to 15℃.

8. The method for preparing crystal form A of the 7-amino-3-(1-pyridinemethyl)cephalosporin hydroiodide monohydrate according to claim 1, characterized in that, In step (C), hydrochloric acid or hydroiodic acid aqueous solution is used as the dissolving solution for dissolution; The dissolution temperature is -5~15℃; In step (C), the iodine salt replacement agent is potassium iodide, sodium iodide, or lithium iodide.

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