Pharmaceutical preparation of cefminox sodium compound and preparation method thereof

Abstract

The invention provides a pharmaceutical preparation of a cefminox sodium compound and a preparation method thereof, belonging to the technical field of drug synthesis. The preparation method comprises the following steps: using 7-MAC as a raw material, sequentially performing an acylation reaction and a decarboxylation protecting group reaction to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid; mixing 460g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid, 235g of D-cysteine ​​hydrochloride and 1.5L of water, performing ultrasonic oscillation, adding 4-10g of anthocyanin and 4-8g of polyvinyl alcohol, wherein the frequency of the ultrasonic oscillation decreases gradually within 80KHZ-45KHZ and the duration is 2h, to obtain a reaction solution; and purifying the reaction solution through a Diaion HP-20 column, concentrating the reaction solution under reduced pressure to dryness, cooling the reaction solution, and precipitating a solid to obtain the cefminox sodium compound. The cefminox sodium crystals prepared by the present invention have strong adaptability to the storage environment, the crystal particle size distribution will not easily change in a short period of time, the crystal particle size distribution has good stability, and the quality is stable and guaranteed.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a pharmaceutical preparation of a cefminox sodium compound and a preparation method thereof. Background Art

[0002] Cefminox sodium generally exists in the form of heptahydrate crystals, and its molecular formula is: C 16 H 20 N7NaO7S3·7H2O, molecular weight 667.67, its structural formula is:

[0003]

[0004] Cefminox sodium is a third-generation cephalosporin antibiotic and a semi-synthetic cephalomycin derivative with a dual mechanism of action. Like other cephalosporins, it has a high affinity for penicillin-binding protein (PBP), with which it can inhibit cell wall synthesis. It also has a unique mechanism of action on peptidoglycan. The D-cysteine ​​at the terminal 7β-side chain binds to peptidoglycan, inhibiting the binding of lipoproteins (proteins that bind peptidoglycan to the outer membrane) to peptidoglycan, causing spherical protrusions to form on the cell wall. This results in a strong bacteriolytic effect, achieving a rapid bactericidal effect.

[0005] Among the synthetic methods reported in existing literature, one involves a route using 7-MAC as the starting material. This route involves reacting 7-MAC with bromoacetyl bromide using N,N-dimethylaniline as an acid-binding agent. The amino group at position 7 of 7-MAC is acylated, and then, in the presence of trifluoroacetic acid, the carboxyl group is removed and condensed with D-cysteine ​​hydrochloride to yield the target compound. This process offers a simple synthetic route with short reaction steps and mild conditions. For example, Chinese patent publication number CN104031070B discloses a method for synthesizing cefminox sodium that employs this synthetic route. However, the cefminox sodium crystals produced by this synthetic route suffer from poor stability and are difficult to store. Especially in high humidity and high temperature environments, the crystal size distribution can easily shift over a short period of time, affecting quality. Summary of the Invention

[0006] In order to solve the problems existing in the background technology, the present invention provides a pharmaceutical preparation of a cefminox sodium compound and a preparation method thereof, so that the prepared cefminox sodium crystals have strong adaptability to the storage environment, good crystal particle size distribution stability, and stable and guaranteed quality.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] A preparation method of a cefminox sodium compound comprises the following steps: using 7-MAC as a raw material, first performing an acylation reaction, and then performing a decarboxylation protecting group reaction to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid;

[0009] 460 g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)sulfurmethyl-3-cephem-4-carboxylic acid, 235 g of D-cysteine ​​hydrochloride and 1.5 L of water were mixed to obtain a mixed solution. Under ultrasonic oscillation conditions, 4-10 g of anthocyanin and 4-8 g of polyvinyl alcohol were successively added to the mixed solution. The frequency of the ultrasonic oscillation was gradually decreased within 80 kHz to 45 kHz. The ultrasonic oscillation reaction lasted for 2 h to obtain a reaction solution.

[0010] The reaction solution is purified by a Diaion HP-20 column, the eluent is collected, concentrated to dryness under reduced pressure, cooled, and a solid is precipitated to obtain a cefminox sodium compound.

[0011] The present invention adds anthocyanins and polyvinyl alcohol to the condensation reaction system. The polyvinyl alcohol can increase the viscosity of the system to a certain extent, which is conducive to the uniform dispersion and retention of anthocyanins in the ultrasonic oscillation system and adsorption at the interface of the condensation product, thereby forming an interface film with uniform texture, so that the interfacial free energy of the condensation product tends to be balanced and stable, ensuring that the interface of the crystal precipitated in the later stage is stable, thereby improving the adaptability of the crystal to the storage environment, effectively preventing the crystal particle size distribution from easily changing in an environment with high humidity and high temperature, and ensuring that the crystal particle size distribution is stable and the quality is stable and guaranteed.

[0012] Furthermore, the amount of anthocyanin added is 8 g, and the amount of polyvinyl alcohol added is 5 g.

[0013] Through the experimental comparison of the examples and comparative examples, it is obtained that the specific dosage of the anthocyanins and polyvinyl alcohol mentioned above has the best crystal size distribution stability.

[0014] Furthermore, during the ultrasonic oscillation reaction process, the control steps of the ultrasonic oscillation frequency are specifically as follows: A1, the frequency of ultrasonic oscillation is 80KHZ for 35 minutes; A2, the frequency of ultrasonic oscillation is 70KHZ for 30 minutes; A3, the frequency of ultrasonic oscillation is 60KHZ for 25 minutes; A4, the frequency of ultrasonic oscillation is 50KHZ for 20 minutes; A5, the frequency of ultrasonic oscillation is 45KHZ for 10 minutes.

[0015] Through the above technical solution, it is ensured that the oscillation frequency decreases step by step during the ultrasonic oscillation reaction, which is conducive to the restoration of the final interface of the precipitated crystals to their original state and the restoration of the stability of the original interface; if the oscillation frequency remains unchanged here, it is not conducive to the restoration of the final interface of the precipitated crystals to their original state and the restoration of the interface stability; if the oscillation frequency increases, the precipitated crystals may be transformed into an uneven cellular interface, or even develop into dendrites, which have poor stability, and the crystal particle size distribution is prone to change during the subsequent storage process, affecting the quality.

[0016] Furthermore, during the ultrasonic oscillation reaction, the pH of the mixed solution was adjusted to 6.7 using 10% sodium bicarbonate solution.

[0017] Further, the specific operation steps of the acylation reaction are as follows: 314g of 7-MAC raw material and 5L of ethyl acetate were stirred and dissolved, 140mL of N, N-dimethylaniline was added at 20°C, 100mL of bromoacetyl bromide was added dropwise in an ice bath, stirred for 10min, 30mL of ice water was added, and extracted three times with ethyl acetate. The organic layers were combined and washed sequentially with ice-cold saturated potassium bisulfate solution 4L×3, ice water 4L, and ice-cold saturated sodium bicarbonate 4L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to recover the solvent. The residue was purified by silica gel column, the desired eluent was collected, and concentrated under reduced pressure to obtain 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester.

[0018] Furthermore, in the silica gel column, the eluent includes toluene and ethyl acetate, and the volume ratio of toluene to ethyl acetate is 5:4.

[0019] Further, the specific operation steps of the decarboxylation protecting group reaction are as follows: 120g of the 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and 1L of anisole were mixed and stirred to dissolve. Under ice bath cooling, 1.25L of trifluoroacetic acid was added and stirred for reaction for 0.5h; the solvent was recovered under reduced pressure, 5L of ethyl acetate was added to the residue, stirred to dissolve, and extracted twice with 10% dipotassium hydrogen phosphate aqueous solution. The aqueous layers were combined, 5L of ethyl acetate was added to the aqueous layer, and the pH was adjusted to 2 with 5mol / L hydrochloric acid under ice bath cooling. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed and the solvent was recovered to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid.

[0020] Furthermore, the cefminox sodium compound is recrystallized with water-acetone to obtain a fine product of cefminox sodium.

[0021] A pharmaceutical preparation of a cefminox sodium compound comprises the cefminox sodium compound prepared by the above-mentioned preparation method.

[0022] This application has the following beneficial effects:

[0023] 1. The present invention uses anthocyanins and polyvinyl alcohol in the condensation reaction system to make the interfacial free energy of the condensation products tend to be balanced and stable, ensuring that the interface of the crystals precipitated later is stable, thereby improving the adaptability of the crystals to the storage environment, effectively preventing the crystal size distribution from easily changing in an environment with high humidity and high temperature, and ensuring good stability of the crystal size distribution and stable quality.

[0024] 2. During the ultrasonic oscillation reaction, the oscillation frequency decreases step by step, which is conducive to the restoration of the final interface of the precipitated crystals to their original state and the stability of the original interface; it prevents the precipitated crystals from being transformed into uneven cellular interfaces or even developing into dendrites, which affects the storage stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The particle size distribution diagram of the products obtained for Examples 1 to 5;

[0026] Figure 2 This is a comparison chart of the particle size distribution of the product obtained in Example 1 before and after storage;

[0027] Figure 3 This is a comparison chart of the particle size distribution of the product obtained in Comparative Example 1 before and after storage;

[0028] Figure 4 This is a comparison chart of the particle size distribution of the product obtained in Comparative Example 2 before and after storage;

[0029] Figure 5 This is a comparison chart of the particle size distribution of the product obtained in Comparative Example 3 before and after storage;

[0030] Figure 6 This is a comparison chart of the particle size distribution of the product obtained in Comparative Example 4 before and after storage. DETAILED DESCRIPTION

[0031] The present application is further described in detail below with reference to the embodiments.

[0032] Unless otherwise specified, the raw materials used in the examples and comparative examples of the present application are all commercially available. Example 1

[0033] A method for preparing a cefminox sodium compound comprises the following steps:

[0034] Preparation of bromoacetyl bromide: Add 0.6 kg (10 mol) of glacial acetic acid and 0.1 kg of red phosphorus (pre-dried at 105°C for 2 h) to a reaction flask and stir. Add 2.7 kg (16.9 mol) of bromine dropwise. If the bromine color does not fade after 1 / 2 of the bromine has been added, heat and illuminate (300W) until the bromine addition is complete. Continue heating to approximately 140°C and stir for 2 h. Cool and distill. Collect the fraction between 146°C and 152°C to obtain bromoacetyl bromide.

[0035] Preparation of 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester: In a reaction flask, 314 g of 7-MAC raw material (7β-amino-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester) and 5 L of ethyl acetate were stirred and dissolved. At 20 ° C, 140 mL of N, N-dimethylaniline was added. Under ice cooling, 100 mL of bromoacetyl bromide was added dropwise, stirred for 10 minutes, and ice water was added. 30mL, extracted three times with ethyl acetate, combined the organic layers, washed successively with ice-cold saturated potassium bisulfate solution 4L×3, ice water 4L, and ice-cold saturated sodium bicarbonate 4L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to recover the solvent, and the residue was purified by silica gel column, in which the eluent included toluene and ethyl acetate, and the volume ratio of toluene and ethyl acetate was 5:4, the desired eluent was collected, and concentrated under reduced pressure to give 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)sulfurmethyl-3-cephem-4-carboxylic acid diphenylmethyl ester.

[0036] Preparation of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid: In a reaction flask, 120g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and 1L of anisole were mixed and stirred to dissolve. 1.25L of trifluoroacetic acid was added under ice cooling and the reaction was stirred for 0.5h. The solvent was recovered under reduced pressure and 5L of the residue was added. Ethyl acetate, stirred and dissolved, extracted twice with 10% dipotassium hydrogen phosphate aqueous solution, combined the aqueous layers, added 5L of ethyl acetate to the aqueous layer, cooled in an ice bath with 5mol / L hydrochloric acid to adjust the pH to 2, separated the organic layer, and extracted the aqueous layer twice with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to recover the solvent to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid.

[0037] Preparation of a cefminox sodium compound: 460 g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid, 235 g of D-cysteine ​​hydrochloride and 1.5 L of water are mixed to obtain a mixed solution; 8 g of anthocyanin and 5 g of polyvinyl alcohol are sequentially added to the mixed solution under ultrasonic oscillation conditions, the frequency of the ultrasonic oscillation being gradually decreased within a range of 80 kHz to 45 kHz; the pH of the mixed solution is adjusted to 6.7 with a 10% sodium bicarbonate solution; the ultrasonic oscillation reaction is continued for 2 hours to obtain a reaction solution; the reaction solution is purified by a Diaion HP-20 column, the eluent is collected, and the reaction solution is concentrated under reduced pressure to dryness, cooled, and a solid is precipitated to obtain the cefminox sodium compound, which is still a crude product at this time. The crude product is further recrystallized from water-acetone to obtain a refined product.

[0038] During the ultrasonic oscillation reaction process, the control steps of the ultrasonic oscillation frequency are specifically as follows: A1, the frequency of ultrasonic oscillation is 80KHZ for 35 minutes; A2, the frequency of ultrasonic oscillation is 70KHZ for 30 minutes; A3, the frequency of ultrasonic oscillation is 60KHZ for 25 minutes; A4, the frequency of ultrasonic oscillation is 50KHZ for 20 minutes; A5, the frequency of ultrasonic oscillation is 45KHZ for 10 minutes. Example 2

[0039] The difference between this embodiment and embodiment 1 is that:

[0040] During the preparation of the cefminox sodium compound, 4 g of anthocyanin and 8 g of polyvinyl alcohol were added to the mixed solution under ultrasonic oscillation. Example 3

[0041] The difference between this embodiment and embodiment 1 is that:

[0042] During the preparation of the cefminox sodium compound, 10 g of anthocyanin and 4 g of polyvinyl alcohol were added to the mixed solution under ultrasonic oscillation. Example 4

[0043] The difference between this embodiment and embodiment 1 is that:

[0044] During the preparation of the cefminox sodium compound, 7 g of anthocyanin and 6 g of polyvinyl alcohol were added to the mixed solution under ultrasonic oscillation. Example 5

[0045] The difference between this embodiment and embodiment 1 is that:

[0046] During the ultrasonic oscillation reaction process, the control steps of the ultrasonic oscillation frequency are specifically as follows: A1, the frequency of ultrasonic oscillation is 80KHZ for 30 minutes; A2, the frequency of ultrasonic oscillation is 75KHZ for 30 minutes; A3, the frequency of ultrasonic oscillation is 65KHZ for 30 minutes; A4, the frequency of ultrasonic oscillation is 55KHZ for 20 minutes; A5, the frequency of ultrasonic oscillation is 45KHZ for 10 minutes.

[0047] Comparative Example 1

[0048] The only difference between this comparative example and Example 1 is that no anthocyanin was added during the preparation of the cefminox sodium compound. The specific steps are as follows:

[0049] Preparation of bromoacetyl bromide: Add 0.6 kg (10 mol) of glacial acetic acid and 0.1 kg of red phosphorus (pre-dried at 105°C for 2 h) to a reaction flask and stir. Add 2.7 kg (16.9 mol) of bromine dropwise. If the bromine color does not fade after 1 / 2 of the bromine has been added, heat and illuminate (300W) until the bromine addition is complete. Continue heating to approximately 140°C and stir for 2 h. Cool and distill. Collect the fraction between 146°C and 152°C to obtain bromoacetyl bromide.

[0050] Preparation of 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester: In a reaction flask, 314 g of 7-MAC raw material (7β-amino-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester) and 5 L of ethyl acetate were stirred and dissolved. At 20 ° C, 140 mL of N, N-dimethylaniline was added. Under ice cooling, 100 mL of bromoacetyl bromide was added dropwise, stirred for 10 minutes, and ice water was added. 30mL, extracted three times with ethyl acetate, combined the organic layers, washed successively with ice-cold saturated potassium bisulfate solution 4L×3, ice water 4L, and ice-cold saturated sodium bicarbonate 4L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to recover the solvent, and the residue was purified by silica gel column, in which the eluent included toluene and ethyl acetate, and the volume ratio of toluene and ethyl acetate was 5:4, the desired eluent was collected, and concentrated under reduced pressure to give 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)sulfurmethyl-3-cephem-4-carboxylic acid diphenylmethyl ester.

[0051] Preparation of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid: In a reaction flask, 120g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and 1L of anisole were mixed and stirred to dissolve. 1.25L of trifluoroacetic acid was added under ice cooling and the reaction was stirred for 0.5h. The solvent was recovered under reduced pressure and 5L of the residue was added. Ethyl acetate, stirred and dissolved, extracted twice with 10% dipotassium hydrogen phosphate aqueous solution, combined the aqueous layers, added 5L of ethyl acetate to the aqueous layer, cooled in an ice bath with 5mol / L hydrochloric acid to adjust the pH to 2, separated the organic layer, and extracted the aqueous layer twice with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to recover the solvent to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid.

[0052] Preparation of a cefminox sodium compound: 460 g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid, 235 g of D-cysteine ​​hydrochloride and 1.5 L of water are mixed to obtain a mixed solution; 5 g of polyvinyl alcohol is added to the mixed solution under ultrasonic oscillation conditions, the frequency of the ultrasonic oscillation being gradually decreased within a range of 80 kHz to 45 kHz; the pH of the mixed solution is adjusted to 6.7 with a 10% sodium bicarbonate solution; the ultrasonic oscillation reaction is continued for 2 hours to obtain a reaction solution; the reaction solution is purified by a Diaion HP-20 column, the eluent is collected, and the reaction solution is concentrated under reduced pressure to dryness, cooled, and a solid is precipitated to obtain the cefminox sodium compound, which is still a crude product at this time. The crude product is further recrystallized from water-acetone to obtain a refined product.

[0053] During the ultrasonic oscillation reaction process, the control steps of the ultrasonic oscillation frequency are specifically as follows: A1, the frequency of ultrasonic oscillation is 80KHZ for 35 minutes; A2, the frequency of ultrasonic oscillation is 70KHZ for 30 minutes; A3, the frequency of ultrasonic oscillation is 60KHZ for 25 minutes; A4, the frequency of ultrasonic oscillation is 50KHZ for 20 minutes; A5, the frequency of ultrasonic oscillation is 45KHZ for 10 minutes.

[0054] Comparative Example 2

[0055] The only difference between this comparative example and Example 1 is that no polyvinyl alcohol was added during the preparation of the cefminox sodium compound. The specific steps are as follows:

[0056] Preparation of bromoacetyl bromide: Add 0.6 kg (10 mol) of glacial acetic acid and 0.1 kg of red phosphorus (pre-dried at 105°C for 2 h) to a reaction flask and stir. Add 2.7 kg (16.9 mol) of bromine dropwise. If the bromine color does not fade after 1 / 2 of the bromine has been added, heat and illuminate (300W) until the bromine addition is complete. Continue heating to approximately 140°C and stir for 2 h. Cool and distill. Collect the fraction between 146°C and 152°C to obtain bromoacetyl bromide.

[0057] Preparation of 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester: In a reaction flask, 314 g of 7-MAC raw material (7β-amino-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester) and 5 L of ethyl acetate were stirred and dissolved. At 20 ° C, 140 mL of N, N-dimethylaniline was added. Under ice cooling, 100 mL of bromoacetyl bromide was added dropwise, stirred for 10 minutes, and ice water was added. 30mL, extracted three times with ethyl acetate, combined the organic layers, washed successively with ice-cold saturated potassium bisulfate solution 4L×3, ice water 4L, and ice-cold saturated sodium bicarbonate 4L, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to recover the solvent, and the residue was purified by silica gel column, in which the eluent included toluene and ethyl acetate, and the volume ratio of toluene and ethyl acetate was 5:4, the desired eluent was collected, and concentrated under reduced pressure to give 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)sulfurmethyl-3-cephem-4-carboxylic acid diphenylmethyl ester.

[0058] Preparation of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid: In a reaction flask, 120g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and 1L of anisole were mixed and stirred to dissolve. 1.25L of trifluoroacetic acid was added under ice cooling and the reaction was stirred for 0.5h. The solvent was recovered under reduced pressure and 5L of the residue was added. Ethyl acetate, stirred and dissolved, extracted twice with 10% dipotassium hydrogen phosphate aqueous solution, combined the aqueous layers, added 5L of ethyl acetate to the aqueous layer, cooled in an ice bath with 5mol / L hydrochloric acid to adjust the pH to 2, separated the organic layer, and extracted the aqueous layer twice with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was decompressed to recover the solvent to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid.

[0059] Preparation of a cefminox sodium compound: 460 g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid, 235 g of D-cysteine ​​hydrochloride and 1.5 L of water are mixed to obtain a mixed solution; 8 g of anthocyanin is added to the mixed solution under ultrasonic oscillation conditions, the frequency of the ultrasonic oscillation is gradually decreased within the range of 80 kHz to 45 kHz; the pH of the mixed solution is adjusted to 6.7 with a 10% sodium bicarbonate solution; the ultrasonic oscillation reaction is continued for 2 hours to obtain a reaction solution; the reaction solution is purified by a Diaion HP-20 column, the eluent is collected, and the reaction solution is concentrated under reduced pressure to dryness, cooled, and a solid is precipitated to obtain the cefminox sodium compound, which is still a crude product at this time. The crude product is further recrystallized from water-acetone to obtain a refined product.

[0060] During the ultrasonic oscillation reaction process, the control steps of the ultrasonic oscillation frequency are specifically as follows: A1, the frequency of ultrasonic oscillation is 80KHZ for 35 minutes; A2, the frequency of ultrasonic oscillation is 70KHZ for 30 minutes; A3, the frequency of ultrasonic oscillation is 60KHZ for 25 minutes; A4, the frequency of ultrasonic oscillation is 50KHZ for 20 minutes; A5, the frequency of ultrasonic oscillation is 45KHZ for 10 minutes.

[0061] Comparative Example 3

[0062] The difference between this comparative example and Example 1 is only that:

[0063] During the preparation of the cefminox sodium compound, 3 g of anthocyanin and 3 g of polyvinyl alcohol were added to the mixed solution under ultrasonic oscillation.

[0064] Comparative Example 4

[0065] The difference between this comparative example and Example 1 is only that:

[0066] During the ultrasonic oscillation reaction process, the control steps of the ultrasonic oscillation frequency are specifically as follows: A1, the frequency of ultrasonic oscillation is 45KHZ for 10 minutes; A2, the frequency of ultrasonic oscillation is 50KHZ for 20 minutes; A3, the frequency of ultrasonic oscillation is 60KHZ for 25 minutes; A4, the frequency of ultrasonic oscillation is 70KHZ for 30 minutes; A5, the frequency of ultrasonic oscillation is 80KHZ for 35 minutes.

[0067] Test example

[0068] The particle size distribution test of the products obtained in Examples 1-5 was as follows: Figure 1 As shown;

[0069] The products obtained in Example 1 and Comparative Examples 1-4 were stored in an environment with a temperature of 40°C and a humidity of 75% for 8 hours. The particle size distribution of the products before and after storage was tested. The results were as follows: Figure 2-Figure 6 shown.

[0070] Result Analysis

[0071] Analyze Examples 1-5 and Test Example 1 and combine Figure 1 It can be seen that the product prepared by the preparation method of the present invention has a moderate particle size distribution width (relatively concentrated), and the particle size within the concentrated range is large, and the product quality is good; after multiple productions, the test particle size distribution diagrams have a high degree of overlap, indicating that the preparation method of the present invention is mature, highly controllable, and the batch production quality is stable and guaranteed.

[0072] Analyze Example 1 and Test Example 2 and combine Figure 2 It can be seen that the product prepared by the preparation method of the present invention is stored in an environment of temperature 40°C and humidity 75% (high temperature and high humidity) for 8 hours, and the coincidence of the particle size distribution diagrams of the products before and after storage is relatively high, indicating that the product prepared by the preparation method of the present invention has strong adaptability to the storage environment and good stability of the crystal particle size distribution. In an environment with high humidity and high temperature, the crystal particle size distribution will not change easily, and the quality is stable and guaranteed.

[0073] Analyze Example 1, Comparative Examples 1-4, and Test Example 2 and combine them Figure 2-6 It can be seen that during the preparation process, no anthocyanin was added, no polyvinyl alcohol was added, the amount of anthocyanin and polyvinyl alcohol added was less than the protection range of the present invention, or the ultrasonic oscillation frequency was increased in a stepwise manner, without causing significant changes in the particle size distribution of the obtained product. This indicates that changes in these conditions do not affect the normal crystallization of the product, and these preparation conditions are not decisive factors affecting the particle size distribution of the generated product crystals.

[0074] However, these changes in conditions all resulted in a significant change in the particle size distribution of the product before and after storage for 8 hours in an environment of 40°C and 75% humidity (high temperature and high humidity), which was mainly reflected in: the particle size distribution width became wider, the particle size concentration became worse, and the particle size within the concentrated range became smaller; thus, it can be seen that the addition of anthocyanins and polyvinyl alcohol in the proportion within the protection scope of the present invention and the step-by-step decrease in the ultrasonic oscillation frequency are indispensable and synergistically produce an auxiliary effect. Although they will not directly affect the particle size distribution of the product, they will enhance the adaptability of the product to the storage environment, improve the stability of the crystal particle size distribution, make the product easier to store, and better ensure storage stability and product quality stability.

[0075] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0076] In addition, the various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A method for preparing a cefminox sodium compound, characterized in that: The method comprises the following steps: using 7-MAC as a raw material, first performing an acylation reaction, and then performing a decarboxylation protecting group reaction to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid; 460 g of 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)sulfurmethyl-3-cephem-4-carboxylic acid, 235 g of D-cysteine ​​hydrochloride and 1.5 L of water were mixed to obtain a mixed solution. Under ultrasonic oscillation conditions, 8 g of anthocyanin and 5 g of polyvinyl alcohol were successively added to the mixed solution. The frequency of the ultrasonic oscillation was gradually decreased within a range of 80 kHz to 45 kHz. The ultrasonic oscillation reaction lasted for 2 h to obtain a reaction solution. During the ultrasonic oscillation reaction, the mixed solution was adjusted to a pH of 6.7 with a 10% sodium bicarbonate solution. The ultrasonic oscillation frequency control steps were as follows: A1, the ultrasonic oscillation frequency was 80 kHz for 35 minutes; A2, the ultrasonic oscillation frequency was 70 kHz for 30 minutes; A3, the ultrasonic oscillation frequency was 60 kHz for 25 minutes; A4, the ultrasonic oscillation frequency was 50 kHz for 20 minutes; A5, the ultrasonic oscillation frequency was 45 kHz for 10 minutes; The reaction solution is purified by a Diaion HP-20 column, the eluent is collected, concentrated to dryness under reduced pressure, cooled, and a solid is precipitated to obtain a cefminox sodium compound.

2. The method for preparing the cefminox sodium compound according to claim 1, wherein The specific operating steps of the acylation reaction are as follows: 7-MAC raw material and ethyl acetate are stirred and dissolved, N,N-dimethylaniline is added at 20° C., bromoacetyl bromide is added dropwise in an ice bath, stirred, and extracted three times with ethyl acetate. The organic layers are combined, washed sequentially with an ice-cold saturated potassium bisulfate solution, ice water, and ice-cold saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and the filtrate is decompressed to recover the solvent. The residue is purified by silica gel column and concentrated under reduced pressure to obtain 7β-bromoacetamide-7α-methoxy-3-(l-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester.

3. The preparation method of the cefminox sodium compound according to claim 2, wherein In the silica gel column, the eluent includes toluene and ethyl acetate, and the volume ratio of toluene to ethyl acetate is 5:

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4. The method for preparing the cefminox sodium compound according to claim 2 or 3, wherein The specific operation steps of the decarboxylation protecting group reaction are as follows: mixing the 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester and anisole, stirring to dissolve, adding trifluoroacetic acid, and stirring to react; recovering the solvent under reduced pressure, adding ethyl acetate to the residue, stirring to dissolve, extracting twice with 10% dipotassium hydrogen phosphate aqueous solution, combining the aqueous layers, adding ethyl acetate to the aqueous layers, adjusting the pH to 2 with 5 mol / L hydrochloric acid, separating the organic layers, extracting the aqueous layers twice with ethyl acetate, combining the organic layers, washing with saturated sodium chloride solution, drying over anhydrous magnesium sulfate, filtering, and recovering the solvent from the filtrate under reduced pressure to obtain 7β-bromoacetamide-7α-methoxy-3-(1-methyl-1H-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid.

5. The method for preparing the cefminox sodium compound according to claim 1, wherein The cefminox sodium compound is recrystallized with water-acetone to obtain a fine product of cefminox sodium.

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