Preparation method of piperacillin acid
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of piperacillin acid.
Background
Piperacillin acid is a semi-synthetic aminourea benzyl anti-pseudomonas penicillin. The chemical name is as follows: (2S, 5R, 6R) -3, 3-dimethyl-6- [ (R) -2- (4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido ] -7-oxo-4-thia-1-nitrogen, formula C23H27N5O7S, the structural formula is as follows:
the sodium salt of Piperacillin acid, Piperacillin sodium (Piperacillin sodium), is a semi-synthetic penicillin antibiotic, has broad-spectrum antibacterial effect, and can exert bactericidal effect by inhibiting bacterial cell wall synthesis. Has good antibacterial effect on Enterobacteriaceae bacteria such as Escherichia coli, Proteus, Serratia, Klebsiella, Enterobacter, Citrobacter, Salmonella and Shigella, and other gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, Haemophilus influenzae and Neisseria. The product also has antibacterial activity against enterococcus, group A or group B hemolytic streptococcus, Streptococcus pneumoniae and penicillin-free staphylococcus. Many anaerobic bacteria such as bacteroides fragilis, clostridium and the like are also sensitive to piperacillin. The compound preparation of piperacillin sodium and tazobactam sodium has wide market prospect.
The currently generally adopted synthesis method of piperacillin acid comprises the following steps: 1) acylation reaction: reacting N-ethyl piperazine, trimethylchlorosilane, triethylamine and triphosgene to prepare N-ethyl piperazine acyl chloride; 2) condensation reaction: in the presence of sodium bicarbonate, reacting N-ethyl dioxypiperazine acyl chloride with ampicillin to prepare a piperacillin acid crude product; 3) refining the crude piperacillin acid to obtain a pure product. The synthetic route is as follows:
the process route has the advantages of mild reaction conditions, easily obtained raw materials, high route yield, low cost, contribution to industrial production and the like. But the acylation reaction step has the defects of low conversion rate of the N-ethyl dioxy piperazine, large solvent loss in the reaction process due to the generation of non-condensable gas carbon dioxide in the condensation step, and the like.
Disclosure of Invention
Aiming at the problems, the invention provides a novel preparation method of piperacillin acid. According to the method, pyridine is used for replacing triethylamine in the acylation reaction to serve as an acid-binding agent, 4-dimethylamino pyridine is added to serve as an initiator to improve the reaction activity of triphosgene, and binary weak base is used for replacing unitary weak base in the condensation reaction to reduce the generation of non-condensable gas carbon dioxide, so that the piperacillin is synthesized more efficiently and more environmentally friendly.
The technical scheme of the invention is as follows: a preparation method of piperacillin acid is characterized by comprising the following steps:
1) acylation: adding N-ethyldioxypiperazine, Trimethylchlorosilane (TMCS), pyridine and 4-Dimethylaminopyridine (DAMP) into an organic solvent (preferably dichloromethane), controlling the temperature to be-35 to-15 ℃, adding triphosgene, and reacting for 30 to 60 minutes under the condition of heat preservation; after the reaction is finished, carrying out post-treatment to obtain N-ethyl dioxypiperazine acyl chloride;
2) condensation: adding ampicillin and binary weak base into a mixed solvent of water and ethyl acetate, controlling the temperature to be 25-45 ℃, and dropwise adding an N-ethyl dioxypiperazine acyl chloride solution; after the dripping is finished, piperacillin acid is obtained through post-treatment.
The chemical reaction formula of the invention is as follows:
further, the weight ratio of 4-dimethylamino pyridine to N-ethyl piperazine dioxide is 1:500-1:3000, preferably 1:1000-1: 1500.
Further, the molar ratio of the N-ethyl dioxypiperazine to the trimethylchlorosilane to the pyridine to the triphosgene is 1: 1.0-2.0: 1.0-2.0: 0.3 to 0.5, preferably 1: 1.5: 1.5: 0.4.
further, the binary weak base is calcium carbonate, manganese carbonate and the like, and calcium carbonate is preferred.
Further, the molar ratio of the binary weak base, the N-ethyl dioxypiperazine acyl chloride and the ampicillin is 0.8-2.0: 0.9-1.5: 1, preferably 1.0 to 1.2: 1.1-1.3: 1.
further, the temperature of the triphosgene adding process in the step 1) is preferably-25 ℃ to-20 ℃.
Further, the reaction temperature in the step 2) is preferably 30-40 ℃.
Further, the volume ratio of the mixed solvent of water and ethyl acetate to the water to the ethyl acetate is 1: 1-2, preferably 1: 1.5.
further, the post-treatment in the step 1) is as follows: and (4) carrying out suction filtration, distilling the filtrate under reduced pressure until the filtrate is dry, and adding N-hexane for crystallization to obtain the N-ethyl piperazine chloride.
Further, the post-treatment in the step 2) is as follows: and (3) decolorizing the water layer after layering, adding ethyl acetate and hydrochloric acid to adjust the pH to 3.0-3.5, and cooling to 0-20 ℃ for crystallization. The acidifying crystallization temperature of piperacillin is preferably 5-15 ℃.
According to the method, pyridine is used as an acid-binding agent instead of triethylamine, and a catalytic amount of 4-Dimethylaminopyridine (DMAP) is added as an initiator before triphosgene is added in an acylation reaction, so that the reaction activity of the triphosgene can be effectively improved, and the conversion rate of the N-ethyl dioxypiperazine acyl chloride is improved by about 10%. In the condensation reaction, binary weak base calcium carbonate, manganese carbonate and the like are used for replacing monobasic weak base sodium bicarbonate, the condensation reaction process is weak in alkalinity, so that degradation is reduced, the condensation reaction yield can be improved by about 5%, and the generation of non-condensable gas carbon dioxide can be reduced by 50%.
Compared with the prior art, the invention has the following advantages:
1. triethylamine is used as an acid-binding agent in the acylation reaction, DMAP is added as an initiator, the reaction activity of triphosgene can be effectively improved, and thus the conversion rate of N-ethyl dioxygen piperazine acyl chloride is improved by about 10%;
2. the binary weak base is adopted to replace the unitary weak base sodium bicarbonate, so that the degradation is reduced, the condensation reaction yield can be improved by about 5 percent, and the generation of non-condensable gas carbon dioxide can be reduced by 50 percent;
3. the preparation method is simple, high in product yield (the total yield is improved by about 14%), low in degraded impurity content (the degraded impurity content is reduced by more than 70%), and more suitable for industrial production.
Detailed Description
Example 1: (after improvement)
1) Taking 14.2g (0.10mol) of N-ethyl piperazine, transferring the N-ethyl piperazine into a 500mL three-necked bottle, stirring, adding 200mL dichloromethane, cooling to-25-20 ℃, dropwise adding 16.3g (0.15mol) of TMCS, controlling the temperature to-25-20 ℃, dropwise adding 11.9g (0.15mol) of pyridine, adding 0.018g of DMAP, controlling the temperature to-25-20 ℃, adding 11.9g (0.04mol) of triphosgene in batches, and preserving the temperature for 30-60 minutes for reaction; and after the reaction is finished, performing suction filtration, washing with 30mL of dichloromethane, performing reduced pressure distillation to dryness, adding 100mL of N-hexane for crystallization, performing suction filtration, and drying to obtain 19.3g of N-ethyldioxopiperazinoyl chloride with the yield of 94.3%.
2) Transferring 20.2g (0.05mol) of ampicillin into a 500mL three-necked bottle, adding 100mL of water and 150mL of ethyl acetate, stirring, adding 5.0g of calcium carbonate, controlling the temperature to be 30-35 ℃, dropwise adding (12.3g of N-ethyl dioxypiperazine acyl chloride and 100mL of dichloromethane) solution, and finishing dripping after 50 min; layering, adding 2.0g of activated carbon into a water layer for decolorization, performing suction filtration, adding 200mL of ethyl acetate, adding hydrochloric acid to adjust the pH value to 3.0-3.5, cooling to 5-15 ℃, performing suction filtration, washing with water, and drying to obtain 25.0g of piperacillin acid solid, wherein the yield is 93.2%, and the content of degradation products is 0.08%.
Example 2 (after modification)
1) Taking 14.2g (0.10mol) of N-ethyl dioxopiperazine, transferring the N-ethyl dioxopiperazine into a 500mL three-necked bottle, stirring, adding 200mL of dichloromethane, cooling to-25-20 ℃, dropwise adding 16.50g (0.152mol) of TMCS, controlling the temperature to-25-20 ℃, dropwise adding 12.0g (0.152mol) of pyridine, adding 0.02g of DMAP, controlling the temperature to-25-20 ℃, adding 11.9g (0.04mol) of triphosgene in batches, preserving the temperature for 30-60 minutes, performing suction filtration, washing with 30mL of dichloromethane, performing reduced pressure distillation to dryness, adding 100mL of N-hexane for crystallization, performing suction filtration, and drying to obtain 19.2g of N-ethyl dioxopiperazine acyl chloride with the yield of 93.8%.
2) Transferring 20.2g (0.05mol) of ampicillin into a 500mL three-necked bottle, adding 100mL of water and 150mL of ethyl acetate, stirring, adding 5.2g of calcium carbonate, controlling the temperature to be 30-35 ℃, dropwise adding (12.3g of N-ethyl dioxypiperazine acyl chloride and 100mL of dichloromethane) solution, and finishing dripping after 50 min; layering, adding 2.0g of activated carbon into a water layer for decolorization, performing suction filtration, adding 200mL of ethyl acetate, adding hydrochloric acid to adjust the pH value to 3.0-3.5, cooling to 5-15 ℃, performing suction filtration, washing with water, and drying to obtain 25.1g of piperacillin acid solid, wherein the yield is 93.7%, and the content of degradation products is 0.07%.
Example 3 (after modification)
1) Taking 14.2g (0.10mol) of N-ethyl dioxopiperazine, transferring the N-ethyl dioxopiperazine into a 500mL three-necked bottle, stirring, adding 200mL of dichloromethane, cooling to-25-20 ℃, dropwise adding 16.0g (0.147mol) of TMCS, controlling the temperature to-25-20 ℃, dropwise adding 11.6g (0.147mol) of pyridine, adding 0.02g of DMAP, controlling the temperature to-25-20 ℃, adding 11.9g (0.04mol) of triphosgene in batches, preserving the temperature for 30-60 minutes, performing suction filtration, washing with 30mL of dichloromethane, performing reduced pressure distillation to dryness, adding 100mL of N-hexane for crystallization, performing suction filtration, and drying to obtain 19.1g of N-ethyl dioxopiperazine acyl chloride with the yield of 93.5%.
2) Transferring 20.2g (0.05mol) of ampicillin into a 500mL three-necked bottle, adding 100mL of water and 150mL of ethyl acetate, stirring, adding 5.3g of calcium carbonate, controlling the temperature to be 35-40 ℃, dropwise adding (12.3g of N-ethyl dioxypiperazine acyl chloride and 100mL of dichloromethane) solution, and finishing dripping after 50 min; layering, adding 2.0g of activated carbon into a water layer for decolorization, performing suction filtration, adding 200mL of ethyl acetate, adding hydrochloric acid to adjust the pH value to 3.0-3.5, cooling to 5-15 ℃, performing suction filtration, washing with water, and drying to obtain 25.0g of piperacillin acid solid, wherein the yield is 93.2%, and the content of degradation products is 0.09%.
Comparative example 1: (before improvement)
1) Taking 14.2g (0.10mol) of N-ethyl-dioxopiperazine, transferring the N-ethyl-dioxopiperazine into a 500mL three-necked bottle, stirring, adding 200mL of dichloromethane, cooling to-25-20 ℃, dropwise adding 16.3g (0.15mol) of TMCS, controlling the temperature to-25-20 ℃, dropwise adding 15.2g (0.15mol) of triethylamine, controlling the temperature to-20-25 ℃, adding 11.9g (0.04mol) of triphosgene in batches, keeping the temperature for 30-60 minutes, performing suction filtration, washing with 30mL of dichloromethane, performing reduced pressure distillation to dryness, adding 100mL of N-hexane for crystallization, performing suction filtration, and drying to obtain 17.2g of N-ethyl-dioxopiperazine chloride with the yield of 84.0%.
2) Transferring 20.2g (0.05mol) of ampicillin into a 500mL three-necked bottle, adding 100mL of water and 150mL of ethyl acetate, stirring, adding 5.2g of sodium bicarbonate, controlling the temperature to be 25-30 ℃, dropwise adding (12.3g of N-ethyl dioxopiperazine acyl chloride and 100mL of dichloromethane) solution, and finishing dripping after 50 min; layering, adding 2.0g of activated carbon into a water layer for decolorization, performing suction filtration, adding 200mL of ethyl acetate, adding hydrochloric acid to adjust the pH value to 3.0-3.5, cooling to 5-15 ℃, performing suction filtration, washing with water, and drying to obtain 23.6g of piperacillin acid solid, wherein the yield is 88.1%, and the content of degradation products is 0.31%.
TABLE 1 comparison of the yields and the contents of degraded impurities of the present invention and the comparative examples