A kind of preparation method of piperacillin acid

Abstract

The invention discloses a method for preparing piperacillin acid. The method is different from the traditional acylation reaction sequence. The method adopts the method of first adding triphosgene and a catalytic amount of trimethylchlorosilane, and then adding alkaline resin and DMAP, thereby reducing the use of trimethylchlorosilane and reducing the generation of dioxypiperazinecarbonyl chloride impurities; using solid acyl chloride to improve the purity of acyl chloride and reduce the introduction of impurities and solvents; using recyclable resin as an acid binding agent in the acylation and condensation steps to avoid the generation of hydrochloride and insoluble gas waste, which is more green and environmentally friendly. In the crystallization step, only ethanol is used as a dispersant, and the finished product is produced at one time. The process is simple and can reduce the growth of degradation impurities during the storage process of the product; the crystallization method of adjusting pH and temperature in stages is conducive to the control of the product crystal form and the sufficient precipitation of crystals, thereby facilitating the improvement of the total yield of the reaction.

Description

Technical Field

[0001] The invention relates to a preparation method of piperacillin acid and belongs to the technical field of medicine. Background Art

[0002] Piperacillin acid, molecular formula C 23 H 29 N5O8S, chemically known as (2S,5R,6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monohydrate, appears as a white crystalline powder and is a semi-synthetic penicillin antibiotic that exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. It has excellent antibacterial activity against Enterobacteriaceae and Gram-negative bacteria. The combination of piperacillin sodium and tazobactam sodium, piperacillin sodium and tazobactam sodium, has a promising market. The structural formula of piperacillin acid is as follows:

[0003]

[0004] The common synthesis route of piperacillin acid is to use 4-ethyl-2,3-dioxypiperazine as the starting material, add trimethylsilyl chloride (about 1.3 eq), and then add triethylamine (about 1.2 eq) as an acid-binding agent and catalyst to generate an active intermediate. Then, triphosgene (about 0.35 eq) is added to react to generate 4-ethyl-2,3-dioxypiperazinecarbonyl chloride. Then, ampicillin and 4-ethyl-2,3-dioxypiperazinecarbonyl chloride are reacted in an aqueous solution of sodium bicarbonate, and crystallized in an ethyl acetate-water system to generate piperacillin acid. The reaction process is as follows.

[0005]

[0006] In this route, 4-ethyl-2,3-dioxypiperazinecarbonyl chloride continues to react to form byproducts, and the use of excess trimethylsilyl chloride results in the subsequent production of a large amount of hexamethyldisiloxane as a byproduct. Furthermore, 4-ethyl-2,3-dioxypiperazinecarbonyl chloride reacts as a dichloromethane solution, resulting in a high level of residual dichloromethane in the finished product. Furthermore, while the condensation reaction conditions in this process are mild, the use of sodium bicarbonate as an acid-binding agent produces a large amount of insoluble carbon dioxide gas. The crystallization system also contains ethyl acetate, which can easily lead to the formation of degradation impurities during storage of the finished product. Summary of the Invention

[0007] To address the above-mentioned issues, the present invention provides a method for preparing piperacillin acid. This method differs from the traditional acylation reaction sequence by first adding triphosgene and a catalytic amount of trimethylsilyl chloride, followed by the addition of a basic resin and DMAP. This reduces the use of trimethylsilyl chloride and the generation of dioxypiperazinecarbonyl chloride impurities. The use of solid acyl chloride improves the purity of the acyl chloride and reduces the introduction of impurities and solvents. A recyclable resin is used as an acid-binding agent in the acylation and condensation steps, avoiding the generation of hydrochloride and insoluble gaseous waste, making the process more environmentally friendly. The crystallization step uses only ethanol as a dispersant, resulting in a single-step product. This method simplifies the process and reduces the growth of degradation impurities during product storage. The crystallization method, which involves adjusting the pH and temperature in stages, facilitates control of the product's crystal form and sufficient crystal precipitation, thereby improving the overall yield of the reaction.

[0008] The technical solution of the present invention is: a method for preparing piperacillin acid, which is characterized by comprising the following steps:

[0009] 1) Acylation: 4-ethyl-2,3-dioxypiperazine, triphosgene, and a catalytic amount of trimethylsilyl chloride are added to dichloromethane, and a basic resin is added. The temperature is lowered to -20 to 0°C, 4-dimethylaminopyridine (DMAP) is added, and the reaction is maintained at -10 to 0°C. After the reaction is complete, the resin is separated and evaporated to dryness to obtain 4-ethyl-2,3-dioxypiperazine acid chloride;

[0010] 2) Condensation: Ampicillin and a basic resin are added to a mixed solvent of water and ethyl acetate, and 4-ethyl-2,3-dioxypiperazine chloride is added at a temperature of 30-35°C. During this time, a basic resin is used to maintain the pH at 6.0-8.0. After completion of the reaction, the crude piperacillin solution is obtained by post-treatment;

[0011] 3) Crystallization: Add ethanol to the aqueous phase, add dilute hydrochloric acid dropwise to pH 1.5-2.0, cool and crystallize to obtain the finished piperacillin acid. The synthesis route is as follows:

[0012]

[0013] Furthermore, in the acylation process of step 1), the resin used is a weakly basic anionic resin, and the weight ratio of 4-ethyl-2,3-dioxypiperazine: dichloromethane: strong basic anionic resin is 1: (6-8): (0.8-1.2), preferably 1: 7: (0.9-1.1).

[0014] Furthermore, in the acylation process of step 1), the molar ratio of 4-ethyl-2,3-dioxypiperazine: triphosgene: trimethylsilyl chloride: 4-dimethylaminopyridine is 1: (0.33-0.35): (0.1-0.3): (0.001-0.002), and the preferred molar ratio is 1: 0.34: 0.1: 0.0015.

[0015] Furthermore, in step 2), the weight ratio of ampicillin:ethyl acetate:water is 1:(5-7):(8-10), preferably 1:6:8.

[0016] Furthermore, the resin used in step 2) is a weakly basic anion resin, and the weight ratio of ampicillin to weakly basic anion resin is 1: (0.6-1.0), preferably 1: (0.8-0.9).

[0017] Furthermore, in the condensation process of step 2), the molar ratio of ampicillin to 4-ethyl-2,3-dioxypiperazine chloride is 1:(1.0-1.2), preferably 1:1.05.

[0018] Furthermore, the post-treatment in step 2) is to separate the organic phase, add activated carbon for decolorization, and wash with water.

[0019] Furthermore, in step 3) the crystallization process, by weight, ampicillin: water: ethanol = 1: (10-12): (4-6), preferably 1: 11: 5.

[0020] Furthermore, the crystallization process of step 3) is as follows: controlling the temperature at 30-35°C, adding dilute hydrochloric acid dropwise to a pH of 3-4, keeping warm for 30-40 minutes, then slowly cooling by 15-20°C, and after sufficient crystallization, continuing to add dilute hydrochloric acid dropwise to a pH of 1.5-2.0, continuing to cool to 5-10°C, keeping warm for 30-40 minutes, and filtering.

[0021] The technical effects of the present invention are:

[0022] 1. Based on the traditional synthesis route of 4-ethyl-2,3-dioxypiperazineyl chloride, the method adjusts the order of adding materials to first add dioxypiperazine, triphosgene and a catalytic amount of trimethylchlorosilane, then add the alkaline resin, and then add DMAP. The adjusted order reduces the generation of by-products and greatly reduces the use of trimethylchlorosilane. At the same time, the alkaline resin is used as an acid binding agent to avoid the generation of hydrochloride. There is no solid hazardous waste, and the resin can be recycled, which is more environmentally friendly.

[0023] 2. Using solid acyl chloride to participate in the reaction improves the purity of the acyl chloride, reduces the introduction of impurities and organic solvents, and is beneficial to improving the quality of the finished product; using weakly basic resin instead of carbonate can reduce product degradation and avoid the generation of carbon dioxide, making the synthesis of piperacillin more environmentally friendly;

[0024] 3. By using ethanol and water as crystallization solvents, the residual ethyl acetate in piperacillin is reduced, thereby improving the stability of the product. The crystallization method of adjusting pH and temperature in stages is beneficial to the control of the product crystal form and sufficient crystallization, thereby facilitating the improvement of the overall yield of the reaction (total yield ≥85%). DETAILED DESCRIPTION

[0025] The effects are described below with reference to embodiments.

[0026] Example 1 (after improvement):

[0027] 1) Acylation: 14.2 g of 4-ethyl-2,3-dioxypiperazine (0.1 mol) was added to 100 g of dichloromethane, the temperature was controlled at 0-10°C, 1.1 g of trimethylsilyl chloride (0.01 mol) and 10.1 g of triphosgene (0.034 mol) were added, 14.0 g of a strong basic anion resin was added, the temperature was lowered to -10-0°C, 0.02 g of DMAP was added dropwise, and the mixture was kept warm for 40 minutes. After completion of the reaction, the mixture was filtered and the filtrate was evaporated to dryness to obtain an acyl chloride solid (external standard 19.4 g, yield 94.9%);

[0028] 2) Condensation: Add 36.4 g of ampicillin trihydrate to 310 g of purified water, add 225 g of ethyl acetate, and 30 g of weakly basic anion resin, control the temperature at 30-35°C, add 4-ethyl-2,3-dioxypiperazine acid chloride, and maintain the pH at 7.0-8.0. After the addition, react for 30 minutes, remove the organic phase, add 2.0 g of activated carbon to decolorize the aqueous phase, filter, and wash the carbon with 91 g of water to obtain a crude piperacillin solution.

[0029] 3) Crystallization: 164 g of 95% ethanol was added to the aqueous phase, the temperature was controlled at 30-35° C., dilute hydrochloric acid was added dropwise to a pH of 3-4, and the mixture was incubated for 30-40 min. The temperature was then slowly lowered by 15-20° C. After sufficient crystallization, dilute hydrochloric acid was added dropwise to a pH of 1.5-2.0. The temperature was further lowered to 5-10° C., and the mixture was incubated for 30-40 min. The mixture was filtered off with suction. Washing with ethanol gave the piperacillin acid product, which was dried to give 44.7 g of the product, with a yield of 92.8%. The product was tested for related substances according to the EP Pharmacopoeia method. The product quality and solvent residue results are shown in Table 1.

[0030] Example 2 (after improvement):

[0031] 1) Acylation: 14.2 g of 4-ethyl-2,3-dioxypiperazine (0.1 mol) was added to 100 g of dichloromethane, the temperature was controlled at 0-10°C, 1.3 g of trimethylsilyl chloride and 10.1 g of triphosgene (0.034 mol) were added, 13.9 g of a strong basic anion resin was added, the temperature was lowered to -10-0°C, 0.02 g of DMAP was added dropwise, and the reaction was kept warm for 40 minutes. After the reaction was completed, the reaction was filtered and the filtrate was evaporated to dryness to obtain an acyl chloride solid (external standard 19.2 g, yield 93.9%);

[0032] 2) Condensation: Add 36.1 g of ampicillin trihydrate to 299 g of purified water, followed by 223 g of ethyl acetate and 30 g of a weakly basic anionic resin. Maintain the temperature at 30-35°C and add 4-ethyl-2,3-dioxypiperazine chloride. Maintain the pH at 7.0-8.0. After addition, react for 30 minutes. Remove the organic phase, decolorize the aqueous phase with 2.0 g of activated carbon, filter, and wash the carbon with 101 g of water to obtain a crude piperacillin solution.

[0033] 3) Crystallization: Add 180g of 95% ethanol to the aqueous phase, control the temperature at 30-35°C, add dilute hydrochloric acid dropwise to a pH of 3-4, incubate for 30-40 minutes, then slowly cool by 15-20°C. After sufficient crystallization, continue to add dilute hydrochloric acid dropwise to a pH of 1.5-2.0, continue to cool to 5-10°C, incubate for 30-40 minutes, and filter with suction. Wash with ethanol to obtain the finished piperacillin acid. Drying yields 44.8g, a yield of 93.0%. Test for related substances according to the EP Pharmacopoeia method. The product quality and solvent residue results are shown in Table 1.

[0034] Example 3 (after improvement):

[0035] 1) Acylation: 14.2 g of 4-ethyl-2,3-dioxypiperazine (0.1 mol) was added to 100 g of dichloromethane, the temperature was controlled at 0-10°C, 1.2 g of trimethylsilyl chloride and 10.1 g of triphosgene (0.034 mol) were added, 14.2 g of a strong basic anion resin was added, the temperature was lowered to -10-0°C, 0.02 g of DMAP was added dropwise, and the reaction was kept warm for 40 minutes. After the reaction was completed, the reaction was filtered and the filtrate was evaporated to dryness to obtain an acyl chloride solid (external standard 19.3 g, yield 94.4%).

[0036] 2) Condensation: Add 36.2 g of ampicillin trihydrate to 312 g of purified water, followed by 228 g of ethyl acetate and 30 g of a weakly basic anionic resin. Maintain the temperature at 30-35°C and add 4-ethyl-2,3-dioxypiperazine chloride. Maintain the pH at 7.0-8.0. After the addition, react for 30 minutes. Remove the organic phase, decolorize the aqueous phase with 2.0 g of activated carbon, filter, and wash the carbon with 83 g of water to obtain a crude piperacillin solution.

[0037] 3) Crystallization: Add 200g of 95% ethanol to the aqueous phase, control the temperature at 30-35°C, add dilute hydrochloric acid dropwise to a pH of 3-4, incubate for 30-40 minutes, then slowly cool by 15-20°C. After sufficient crystallization, continue to add dilute hydrochloric acid dropwise to a pH of 1.5-2.0, continue to cool to 5-10°C, incubate for 30-40 minutes, and filter with suction. Wash with ethanol to obtain the finished piperacillin acid. Drying yields 44.9g, a yield of 93.3%. Test for related substances according to the EP Pharmacopoeia method. The product quality and solvent residue results are shown in Table 1.

[0038] Control example (before improvement):

[0039] 1) Acylation: 14.2 g of 4-ethyl-2,3-dioxypiperazine was added to 100 g of dichloromethane, cooled to 0-10° C., 14.1 g of trimethylsilyl chloride (0.13 mol) was added, cooled to -10-0° C., 12.1 g of triethylamine (0.12 mol) was added dropwise, and 10.4 g of triphosgene (0.035 mol) was added at the same temperature. The mixture was kept warm for 40 minutes, and the filter cake was separated by filtration to obtain a dichloromethane solution of 4-ethyl-2,3-dioxypiperazine acid chloride, which was concentrated for later use (external standard 18 g, yield 88.1%);

[0040] 2) Condensation: Add 300 g of water, 135 g of ethyl acetate, and 33.8 g (0.084 mol) of ampicillin trihydrate to a reaction flask, control the temperature at 20-30°C, add 20 g of sodium bicarbonate, and dropwise add a dichloromethane solution of 4-ethyl-2,3-dioxypiperazineyl chloride. Separate the layers and decolorize the aqueous layer with 2.0 g of activated carbon.

[0041] 3) Refining: After decolorization, filter with suction, wash the charcoal with 60 g of water, add 200 g of ethyl acetate to the aqueous layer, control the temperature at 15-20°C, dropwise add dilute hydrochloric acid to adjust the pH to 1.8, incubate for 90 min, filter with suction, and dry to obtain 39.4 g, with a yield of 87.8%. The relevant substances were tested according to the EP Pharmacopoeia method. The product quality and solvent residue results are shown in Table 1.

[0042] Table 1 Results of residual solvents in products of Examples 1-3 and Control Examples

[0043] ethanol dichloromethane Ethyl acetate Silicon ether Total yield Example 1 2903ppm 74ppm 154ppm 0ppm 88.1％ Example 2 3156ppm 68ppm 121ppm 0ppm 87.3％ Example 3 3479ppm 75ppm 114ppm 0ppm 88.1％ Control Example 0ppm 348ppm 7436ppm 67ppm 77.3％

[0044] As can be seen from Table 1, the product of the control example contains residual dichloromethane, silyl ether, and ethyl acetate, while the product of the present invention avoids the use of ethyl acetate in the crystallization step, and the residual ethyl acetate in the finished product is very low; the use of solid acyl chloride reduces the introduction of dichloromethane and trimethylchlorosilane into the acyl chloride feed liquid, greatly reduces the residual silyl ether and dichloromethane in the finished product, improves the product quality, and increases the total yield of the product by more than 10%.

[0045] The piperacillin acid products obtained in Examples 1-3 and the reference examples were sealed and packaged in double-layer polyethylene plastic bags with U-shaped ties. The bags were then placed in a constant temperature drying oven at 40±2°C and a relative humidity of 75±5%. The samples were taken out at 0, 1, 2, 3, and 6 months, respectively, and the contents were determined by high performance liquid chromatography (HPLC). The piperacillin degradation of Examples 1-3 and the reference examples was determined under accelerated test conditions. The results are shown in Table 2.

[0046] Table 2 Stability test results

[0047]

[0048]

[0049] Through stability tests, it can be found that the piperacillin acid of the present invention has good stability during the preparation and storage processes, can effectively control the impurity level, and ensure the efficacy of the product.

Claims

1. A method for preparing piperacillin acid, characterized in that: The following steps are involved: 1) Acylation: 4-ethyl-2,3-dioxypiperazine, triphosgene and a catalytic amount of trimethylsilyl chloride are added to dichloromethane, a strong basic anion resin is added, the temperature is lowered to -20 to 0°C, 4-dimethylaminopyridine is added, and the temperature is kept at -10 to 0°C for reaction. After the reaction is completed, the resin is separated and evaporated to dryness to obtain 4-ethyl-2,3-dioxypiperazine acyl chloride; in terms of molar ratio, 4-ethyl-2,3-dioxypiperazine: triphosgene: trimethylsilyl chloride: 4-dimethylaminopyridine = 1: (0.33 to 0.35): (0.1 to 0.3): (0.001 to 0.002); in terms of weight, 4-ethyl-2,3-dioxypiperazine: dichloromethane: strong basic anion resin = 1: (6 to 8): (0.8 to 1.2); 2) Condensation: adding ampicillin and weakly basic anion resin to a mixed solvent of water and ethyl acetate, adding solid 4-ethyl-2,3-dioxypiperazine chloride at a temperature of 30-35° C., maintaining the pH at 6.0-8.0 with a weakly basic anion resin, separating the organic phase after the reaction, adding activated carbon for decolorization, and washing with water to obtain a piperacillin crude product solution; by weight, ampicillin:weakly basic anion resin=1:(0.6-1.0); 3) Crystallization: Add 95% ethanol to the aqueous phase to control the temperature at 30-35°C, add dilute hydrochloric acid dropwise to pH 3-4, keep warm for 30-40 min, then slowly cool down by 15-20°C, continue to add dilute hydrochloric acid dropwise to pH 1.5-2.0 after sufficient crystallization, continue to cool to 5-10°C, keep warm for 30-40 min, filter and obtain piperacillin acid.

2. The method for preparing piperacillin acid according to claim 1, wherein: In the step 2), the weight ratio of ampicillin:ethyl acetate:water is 1:(5-7):(8-10).

3. The method for preparing piperacillin acid according to claim 1, wherein: In the condensation process of step 2), the molar ratio of ampicillin to 4-ethyl-2,3-dioxypiperazine chloride is 1:(1.0-1.2).

4. The method for preparing piperacillin acid according to claim 1, wherein: During the crystallization process, by weight, ampicillin: water: 95% ethanol = 1: (10-12): (4-6).

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