Preparation method of sutacillin

Abstract

The invention discloses a preparation method of sutacillin, and belongs to the technical field of biological medicines. The preparation method of the sutacillin comprises the following steps: (1) weighing sutacillin tosilate, adding the sutacillin tosilate into an organic solvent for dissolving, cooling and stirring, dropwise adding an alkali solution, stirring until a system is dissolved, separating liquid, taking an organic phase, adding a dehydrating agent for drying, and filtering to obtain filtrate; and (2) adding a seed crystal into the filtrate obtained in the step (1), carrying out primary vacuum concentration, cooling, stirring and crystallizing, carrying out secondary vacuum concentration, adding an organic solvent when the filtrate is concentrated until no obvious fraction exists, and carrying out gradient cooling and crystal growing, filtering, pumping and vacuum drying to obtain the sutacillin. The sultacillin bulk drug prepared by the method is high in yield, high in purity and stable in chemical property. Moreover, according to the preparation method of the sutacillin, generation of related impurities possibly caused in the crushing process is avoided, the production cost is saved, the production efficiency is high, the particle size of the sutacillin raw material medicine can be effectively controlled, and the dissolution effect is good when the sutacillin raw material medicine is prepared into an oral preparation.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and particularly relates to a method for preparing sultamicillin. Background Art

[0002] The chemical name of sultamicillin is (+) hydroxymethyl-(2S,5R,6R)-6-[(R)-2-amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]n-heptane-2-hydroxy ester (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]n-heptane-2-carboxylate S,S-dioxide. The molecular formula is C 25 H 30 N4O9S2, the structural formula is as follows (Formula I):

[0003]

[0004] Sulbactam is an ester drug formed by combining ampicillin and sulbactam in a 1:1 or 1:2 molar ratio through a diester bond. Among them, ampicillin is a penicillin antibiotic. Sulbactam itself has a weak antibacterial effect and is a competitive, irreversible lactamase inhibitor. When used in combination with the lactam antibiotic ampicillin, a good synergistic effect can be obtained. Sulbactam not only protects ampicillin from hydrolysis and destruction by lactamase, but also expands the antibacterial spectrum of ampicillin.

[0005] Sultamicillin itself has poor stability. It is prone to degradation under high humidity and non-low temperature conditions, resulting in reduced efficacy and drug resistance. The commonly used technology in China is to use p-toluenesulfonic acid to salt sultamicillin tosylate, which slightly improves the stability of the drug, but still needs to be refrigerated, and p-toluenesulfonic acid is easy to form genotoxic impurities, which is not conducive to the safety of drug use.

[0006] In the prior art, US4342772A discloses a method for synthesizing sultamicillin hydrochloride by using penicillanic acid as a raw material, through chloroester formation, oxidation, iodination, esterification and salt formation. US4340539A discloses a method for synthesizing chlorosultamicillin by using chlorosulbactam acid as a raw material, through chloroester formation, iodination and esterification. CN112724162 discloses a method for synthesizing amoxicillin-sulbactam hybrid molecule hydrochloride by using sulbactam acid as a starting material, through chloroester formation, iodination and esterification. The prior art mainly discloses a method for preparing sultamicillin salt compounds, and it is necessary to develop a new method for preparing sultamicillin raw materials. Summary of the invention

[0007] In view of the problems existing in the above-mentioned prior art, the purpose of the present invention is to provide a method for preparing sultamicillin. The sultamicillin raw material prepared by the present invention has high yield, high purity and stable chemical properties.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] In one aspect, the present invention provides a method for preparing sultamicillin, comprising the following steps:

[0010] (1) Weighing sultamicillin tosirate, adding it to an organic solvent to dissolve, cooling and stirring, adding an alkali solution dropwise, stirring until the system is dissolved and clear, separating the liquids, taking the organic phase, adding a dehydrating agent to dry it, and filtering to obtain a filtrate;

[0011] (2) adding seed crystals to the filtrate obtained in the above step (1), performing a first vacuum concentration, cooling, stirring and crystallizing, performing a second vacuum concentration, adding an organic solvent when no obvious fraction is left, gradually cooling to grow crystals, filtering, draining, and vacuum drying to obtain sultamicillin.

[0012] In the method for preparing sultamicillin, the organic solvent in step (1) is at least one of dichloromethane and ethyl acetate, and preferably the organic solvent is ethyl acetate;

[0013] The alkaline solution is an inorganic alkaline solution, preferably the alkaline solution is at least one of sodium bicarbonate, sodium carbonate, and sodium hydroxide, and more preferably the alkaline solution is at least one of sodium bicarbonate and sodium hydroxide;

[0014] The dehydrating agent is at least one of anhydrous sodium sulfate and anhydrous magnesium sulfate, and preferably the dehydrating agent is anhydrous magnesium sulfate.

[0015] In the method for preparing sultamicillin, in step (1), the mass to volume ratio of sultamicillin tosylate to the organic solvent is 1:20-35 g / mL, and preferably the mass to volume ratio of sultamicillin tosylate to the organic solvent is 1:30 g / mL.

[0016] In the method for preparing sultamicillin, the temperature of cooling and stirring in step (1) is 0-10°C, preferably 0-5°C.

[0017] In the method for preparing sultamicillin, the mass ratio of sultamicillin tosylate to the dehydrating agent in step (1) is 10:3-8, and preferably the mass ratio of sultamicillin tosylate to the dehydrating agent is 2:1.

[0018] In the method for preparing sultamicillin, the mass ratio of the seed crystal to sultamicillin tosylate in step (2) is 0.5 to 2:100, preferably the mass ratio of the seed crystal to sultamicillin tosylate is 1:100;

[0019] The volume to mass ratio of the organic solvent to sultamicillin tosylate is 0.5 to 2:1 mL / g, and preferably the volume to mass ratio of the organic solvent to sultamicillin tosylate is 1:1 mL / g.

[0020] In the method for preparing sultamicillin, the conditions for the first reduced pressure concentration in step (2) are: the first reduced pressure concentration to 45-55%, the temperature is 30-45° C., preferably the temperature is 35-40° C.;

[0021] The stirring crystallization time is 30 minutes;

[0022] The temperature of the second reduced pressure concentration is 20-30°C, preferably 25°C.

[0023] In the method for preparing sultamicillin, the gradient cooling crystal growing in step (2) is specifically: first cooling to 10-20°C for the first crystal growing for 30 minutes, and then cooling to -5-5°C for the second crystal growing for 3-8 hours.

[0024] In the method for preparing sultamicillin, the temperature of the first crystal growing is 10-15°C, and the temperature of the second crystal growing is 0-5°C.

[0025] Application of any one of the preparation methods in the preparation of high-purity sultamicillin.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The sultamicillin raw material drug prepared by the present invention has high yield, high purity and stable chemical properties. In addition, the preparation method and refining process of sultamicillin of the present invention saves the crushing and granulating process, avoids the generation of related impurities that may be caused by the crushing process, saves production costs, improves production efficiency, and effectively controls the particle size of the sultamicillin raw material drug through the optimization of the crystallization process, so that the dissolution effect is good when the oral preparation is prepared. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The present invention is a flow chart of the preparation method of sultamicillin. DETAILED DESCRIPTION

[0029] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0030] Example 1: Preparation of Sultamicillin Tosirate

[0031] (1) Preparation of sulbactam chloromethyl ester: Add 6.0 kg of purified water to a reactor, cool to about 10-15°C, add 1.0 kg of sulbactam acid, slowly add 1.3 kg of sodium bicarbonate, stir for 10 minutes after addition, then add 5.0 kg of dichloromethane, then add 50.0 g of tetrabutylammonium hydrogen sulfate, dropwise add 1.1 kg of chloromethyl chlorosulfonate + 2.0 kg of dichloromethane, control the internal temperature not higher than 10-25°C, after the addition is complete, cool to 5-10°C, react for 2 hours, and keep warm. After standing and stratifying, the aqueous layer was extracted with 3 kg of dichloromethane, the organic phases were combined, 5 kg of purified water was added to the reaction bottle, the temperature was lowered to 0-5°C, the organic phase was added to the reaction bottle, stirred for 10 minutes, allowed to stand and stratify, the aqueous layer was discarded, and the organic phase was added to the reaction bottle again. After the organic phase was concentrated until there was no obvious fraction, 5.0 kg of isopropanol was added, and the mixture was slurried and crystallized at 0-5°C for 2 hours, filtered, and the wet product was vacuum dried at 35°C for 20 hours to obtain 1.1 kg of sulbactam chloromethyl ester with a molar yield of 90.9%.

[0032] (2) Preparation of sulbactam iodine methyl ester: 7.0 kg of acetone was added to a reaction kettle, followed by 1.0 kg of sulbactam chloromethyl ester, and 0.8 kg of sodium iodide was slowly added. The temperature was raised to 55-65° C. for reaction for 4 hours. After the reaction, the reaction system was cooled to 20-25° C., saturated sodium bicarbonate solution was added dropwise, and the pH value was adjusted to about 8.0. Then, about 0.8 kg of 10% sodium thiosulfate aqueous solution was added dropwise. The feed liquid turned white, and the temperature was lowered to 0-10° C. for crystallization for 2 hours. The mixture was filtered and washed with water, and vacuum dried at 35° C. for 20 hours to obtain 1.2 kg of sulbactam iodine methyl ester with a molar yield of 90.4%.

[0033] (3) Preparation of sultamicillin tosirate: Add 0.3 kg of potassium carbonate, 6.0 kg of N,N-dimethylformamide, and 0.8 kg of methyl acetoacetate to a reactor, then add 1.2 kg of ampicillin trihydrate, and react at 25-30°C for 1 hour. Then cool to 0-10°C, add 1.0 kg of sulbactam iodide methyl ester, and react at 0-10°C for 3 hours. Add 3.0 kg of dichloromethane and 10.0 kg of saturated sodium chloride aqueous solution to the reaction solution, stir and separate the liquids, extract the aqueous phase with 2.0 kg of dichloromethane once, and combine the organic phases. Add 1.1 kg of p-toluenesulfonic acid dropwise, and crystallize at 0-10°C for 2 hours. Centrifuge and filter, wash the filter cake with a large amount of water until the pH value is greater than 6, and dry the wet product in vacuum at 40°C for 24 hours to obtain 2.0 kg of sultamicillin tosirate, with a molar yield of 93%.

[0034] Example 2: Preparation of Sultamicillin

[0035] 30.0 g of sultamicillin tosirate prepared in Example 1 and 1000 mL of ethyl acetate were added to the reaction flask, the temperature was lowered to 0° C. and stirred, saturated sodium bicarbonate solution was added dropwise until the solution was clear, and the mixture was stirred for 0.5 h after the addition was completed. The layers were separated, and the organic layer was dried over 15 g of anhydrous magnesium sulfate and filtered.

[0036] Add 0.3g of seed crystals, and start concentrating the filtrate. Concentrate at 40℃ until about 50% of the liquid remains. Then cool to 25℃ and stir for 30min. Continue concentrating at 25℃ until no obvious fraction is found. Add 30mL of ethyl acetate, cool to 10℃ for 30min, and cool to 0℃ for 3h. Filter, drain, and vacuum dry at 50℃ for 12h to obtain 18.0g, with a molar yield of 81.1% and a HPLC purity of 99.40%. Figure 1 The present invention is a flow chart of the preparation method of sultamicillin.

[0037] Example 3: Preparation of Sultamicillin

[0038] 30.0 g of sultamicillin tosirate prepared in Example 1 and 900 mL of ethyl acetate were added to the reaction flask, the temperature was lowered to 5° C. and stirred, saturated sodium bicarbonate solution was added dropwise until dissolved, and stirred for 0.5 h after the addition was complete. The layers were separated, and the organic layer was dried over 15 g of anhydrous magnesium sulfate and filtered.

[0039] 0.4 g of seed crystals were added, and the filtrate began to be concentrated. It was concentrated at 40°C until about 50% of the feed liquid remained. Then the temperature was lowered to 25°C and stirred for crystallization for 30 minutes. At 25°C, the concentration was continued until no obvious fractions were found. 30 mL of ethyl acetate was added, and the temperature was lowered to 15°C for crystallization for 30 minutes, and then to 5°C for crystallization for 6 hours. Filter, drain, and vacuum dry at 50°C for 12 hours to obtain 18.3 g, with a molar yield of 82.4% and a HPLC purity of 99.45%.

[0040] Example 4: Preparation of Sultamicillin

[0041] 30.0 g of sultamicillin tosirate prepared in Example 1 and 600 mL of dichloromethane were added to the reaction flask, the temperature was lowered to 5° C. and stirred, saturated sodium bicarbonate solution was added dropwise until dissolved, and stirred for 0.5 h after the addition was complete. The layers were separated, and the organic layer was dried over 15 g of anhydrous magnesium sulfate and filtered.

[0042] Add 0.3g of seed crystals, and start concentrating the filtrate. Concentrate at 45℃ until about 50% of the liquid remains. Then cool to 25℃ and stir for 30min. Continue concentrating at 25℃ until no obvious fraction is found. Add 30mL of ethyl acetate, cool to 10℃ for 30min, and cool to -5℃ for 8h. Filter, drain, and vacuum dry at 50℃ for 12h to obtain 18.6g, with a molar yield of 83.7% and a HPLC purity of 99.30%.

[0043] Comparative Example 1: Preparation of Sultamicillin

[0044] 30.0 g of sultamicillin tosirate prepared in Example 1 and 600 mL of ethyl acetate were added to the reaction flask, the temperature was lowered to 0° C. and stirred, saturated sodium bicarbonate solution was added dropwise until dissolved, and stirred for 0.5 h after the addition was complete. The layers were separated, and the organic layer was dried over 6 g of anhydrous magnesium sulfate and filtered.

[0045] 0.1 g of sultamicillin was added as a seed crystal, and the organic phase was concentrated under reduced pressure at a concentration temperature of 50°C until there was no obvious fraction. 60 mL of ethyl acetate was added, and the temperature was lowered to 0°C for crystallization for 6 h. The mixture was filtered, dried, and dried under vacuum at 50°C for 12 h to obtain 15.3 g, with a molar yield of 68.9% and an HPLC purity of 98.62%.

[0046] Comparative Example 2: Preparation of Sultamicillin

[0047] 30.0 g of sultamicillin tosirate prepared in Example 1 and 600 mL of dichloromethane were added to the reaction flask, the temperature was lowered to 5° C. and stirred, 10% sodium hydroxide solution was added dropwise until dissolved, and stirred for 0.5 h after the addition was complete. The organic layer was dried over 6 g of anhydrous magnesium sulfate and filtered.

[0048] 0.3 g of sultamicillin was added as a seed crystal, and the organic phase was concentrated under reduced pressure at a concentration temperature of 45°C until there was no obvious fraction. 60 mL of ethyl acetate was added, and the temperature was lowered to 0°C for crystallization for 6 h. The mixture was filtered, dried, and dried in vacuo at 50°C for 12 h to obtain 12.1 g, with a molar yield of 54.5% and an HPLC purity of 94.22%.

[0049] Example 5: Preparation of Sultamicillin Granules

[0050] The sultamicillin bulk drug prepared in Examples 2 to 4 and Comparative Examples 1 and 2 was used to prepare sultamicillin granule preparations in the following manner, wherein the components and proportions are shown in Table 1 below:

[0051] Table 1 Composition and ratio of sultamicillin granules

[0052]

[0053] The prepared preparations are sultamicillin granule preparations 1 to 5. The particle size test of sultamicillin raw material was carried out by laser method. The results are shown in Table 2 below. The test conditions are as follows:

[0054] Instrument: PAQXOSHELOS-RODOS laser particle size analyzer;

[0055] Method: Dry test;

[0056] Spreading pressure: 2Bar;

[0057] Gap width: 2mm.

[0058] And their dissolution curves in pH 4.5 dissolution medium were examined, as shown in Table 3 below.

[0059] Table 2 Particle size of sultamicillin granules 1 to 5

[0060]

[0061]

[0062] The results show that the particle size of the sultamicillin raw materials prepared in Examples 2 to 4 is relatively small, while the particle size of the sultamicillin raw materials prepared in Comparative Examples 1 and 2 is relatively large.

[0063] Table 3 pH 4.5 dissolution curve results

[0064]

[0065] The results show that in the dissolution medium of pH 4.5, the sultamicillin raw material with a small particle size dissolves quickly, while the sultamicillin raw material with a large particle size dissolves slowly.

[0066] Embodiment 6:

[0067] The sultamicillin bulk drug prepared in Example 2 was subjected to a stability test (25±2°C, relative humidity 60±5%). The stability results are shown in Table 4 below:

[0068] Table 4 Stability of Sultamicillin prepared in Example 2

[0069] Inspection items / time Day 0 March June content 98.2％ 97.6％ 97.8％ Total related substances 0.6％ 0.7％ 0.7％

[0070] Conclusion: The content and related substances of the sultamicillin raw material prepared by the present invention remain stable at room temperature and have good chemical stability.

Claims

1. A method for preparing sultamicillin, characterized in that: The following steps are involved: (1) Weighing sultamicillin tosirate, adding it to an organic solvent to dissolve, cooling and stirring, adding an alkali solution dropwise, stirring until the system is dissolved and clear, separating the liquids, taking the organic phase, adding a dehydrating agent to dry it, and filtering to obtain a filtrate; (2) adding seed crystals to the filtrate obtained in the above step (1), performing a first vacuum concentration, cooling, stirring and crystallizing, performing a second vacuum concentration, adding an organic solvent when no obvious fraction is left, gradually cooling to grow crystals, filtering, draining, and vacuum drying to obtain sultamicillin.

2. The method for preparing sultamicillin according to claim 1, characterized in that: The organic solvent in step (1) is at least one of dichloromethane and ethyl acetate, and preferably the organic solvent is ethyl acetate; The alkaline solution is an inorganic alkaline solution, preferably the alkaline solution is at least one of sodium bicarbonate, sodium carbonate, and sodium hydroxide, and more preferably the alkaline solution is at least one of sodium bicarbonate and sodium hydroxide; The dehydrating agent is at least one of anhydrous sodium sulfate and anhydrous magnesium sulfate, and preferably the dehydrating agent is anhydrous magnesium sulfate.

3. The method for preparing sultamicillin according to claim 1, characterized in that: The mass-to-volume ratio of sultamicillin tosylate to the organic solvent in step (1) is 1:20-35 g / mL, and preferably the mass-to-volume ratio of sultamicillin tosylate to the organic solvent is 1:30 g / mL.

4. The method for preparing sultamicillin according to claim 1, characterized in that: The temperature of the cooling and stirring in step (1) is 0-10°C, preferably 0-5°C.

5. The method for preparing sultamicillin according to claim 1, characterized in that: The mass ratio of sultamicillin tosylate to the dehydrating agent in step (1) is 10:3-8, preferably 2:

1.

6. The method for preparing sultamicillin according to claim 1, characterized in that: The mass ratio of the seed crystal to sultamicillin tosirate in step (2) is 0.5 to 2:100, preferably the mass ratio of the seed crystal to sultamicillin tosirate is 1:100; The volume to mass ratio of the organic solvent to sultamicillin tosylate is 0.5 to 2:1 mL / g, and preferably the volume to mass ratio of the organic solvent to sultamicillin tosylate is 1:1 mL / g.

7. The method for preparing sultamicillin according to claim 1, characterized in that: The conditions for the first reduced pressure concentration in step (2) are: the first reduced pressure concentration to 45-55%, the temperature is 30-45° C., preferably the temperature is 35-40° C.; The stirring crystallization time is 30 minutes; The temperature of the second reduced pressure concentration is 20-30°C, preferably 25°C.

8. The method for preparing sultamicillin according to claim 1, characterized in that: The gradient cooling crystal growing in step (2) is specifically as follows: firstly cooling to 10-20°C for the first crystal growing for 30 minutes, and then cooling to -5-5°C for the second crystal growing for 3-8 hours.

9. The method for preparing sultamicillin according to claim 8, characterized in that: The temperature of the first crystal growing process is 10-15°C, and the temperature of the second crystal growing process is 0-5°C.

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of high-purity sultamicillin.

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