Preparation method of penicillin V potassium
The preparation process of penicillin V potassium is simplified by chemical synthesis method, solving the problems of complex and high cost in the existing process, and achieving high yield and high purity penicillin V potassium production.
Patent Information
- Application Number
- CN202510425724.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-07
- Publication Date
- 2025-07-04
AI Technical Summary
The existing penicillin V potassium production process is complex, with many equipment, large power consumption, product quality is affected, and the cost is high. The preparation method needs to be simplified and optimized.
Using chemical synthesis methods, the steps of synthesis of phenoxyacetyl chloride, preparation of penicillin V acid and preparation of penicillin V potassium include the reaction of phenoxyacetic acid, sulfoxide chloride and DMF, the pH value is controlled for condensation reaction, and the use of activated carbon decolorization and salt-forming reaction are prepared.
It achieves simple process, high yield, high product purity, reduces production costs and power consumption, and improves product quality.
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Figure CN120247928A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of drug compound synthesis, and more specifically, relates to a preparation method of potassium penicillin V. Background Art
[0002] Potassium penicillin V, whose structural formula is as follows, belongs to β-lactam antibiotics. Its antibacterial spectrum is similar to that of penicillin G. It can destroy the bacterial cell wall and has a bactericidal effect. Clinically, it has been widely used in the treatment of abscesses, suppurative meningitis, pneumonia, gonorrhea and other diseases. Compared with penicillin G, potassium penicillin V is stable to acid, not destroyed by gastric acid, and has good oral absorption. In addition, it is destroyed by enzymes slower than penicillin G, so it is more effective than penicillin G in treating infections caused by drug-resistant Staphylococcus aureus.
[0003]
[0004] Clinically, potassium penicillin V is applicable to upper and lower respiratory tract infections, otitis media, scarlet fever, erysipelas, tonsillitis, skin and soft tissue infections, gonorrhea and syphilis caused by penicillin-sensitive bacteria. It can also be used for the prevention of rheumatism and bacterial endocarditis.
[0005] Potassium penicillin V tablets were first applied clinically abroad in 1952 and were approved by the US FDA in September 1957. They are included in the United States Pharmacopeia, British Pharmacopoeia, Japanese Pharmacopoeia, etc. Currently, the United States, Canada, the United Kingdom, Germany, Japan and other countries are all producing it, and it is a very widely used oral antibiotic clinically in the world.
[0006] Potassium penicillin V was applied clinically in China as early as the 1950s. Due to the low production strain capacity and unqualified extraction process at that time, it has not been able to be produced and used. In 1982, North China Pharmaceutical began to develop the generic drug of the active pharmaceutical ingredient, and it was successfully developed and put into the domestic market in 1984, thus filling the gap of this product in the domestic market. After 1995, the company carried out further technological transformation and process improvement, resulting in a substantial improvement in the quality of the active pharmaceutical ingredient. In particular, an internal control index of high polymer was added, and the allergic problems of this product in clinical use were controlled in production. In the past, the standards in China were all local standards. After the potassium penicillin V tablets of North China Pharmaceutical passed the safety verification of 10,000 cases by the Ministry of Health in 1997, the quality standard of this product was jointly improved with the National Institute for the Control of Pharmaceutical and Biological Products and implemented as the internal control quality standard of North China Pharmaceutical. In 1998, it applied for and obtained the approval of the ministry-issued standard. The 2000 edition of the Chinese Pharmacopoeia supplemented the active pharmaceutical ingredient and preparations of potassium penicillin V. Another domestic chemical pharmaceutical enterprise, Jiangxi Dongfeng Pharmaceutical Co., Ltd., also started the research on the production process of potassium penicillin V in 1996 and began mass production in 1997.
[0007] At present, the production process of penicillin V potassium is as follows: the penicillin fermentation broth is filtered, acidified and extracted to obtain acid crystal powder, then decolorized, reacted with a salifying agent to form a salt, and then mixed with a lower alcohol, and penicillin V potassium is obtained by azeotropic crystallization. This process requires adding a flocculant and diatomaceous earth to improve the filtration speed, and a demulsifier also needs to be added during the extraction process to achieve the extraction effect. The addition of these substances has a great impact on the product quality; in addition, this process is complex and requires a lot of equipment; the process requires a relatively high temperature and high power consumption. At the same time, people have also studied the preparation of penicillin V potassium by pure chemical synthesis, looking for a preparation method with simple process, easy operation, low cost and low energy consumption to improve the product quality of this product, which is of great significance to this product. Summary of the Invention
[0008] Therefore, the object of the present invention is to provide a method for preparing penicillin V potassium, which uses a chemical synthesis method to prepare penicillin V potassium. This preparation method has a simple process, high yield and good product quality.
[0009] According to the present invention, the method for preparing penicillin V potassium provided by the present invention includes the following steps:
[0010] (1) Synthesis of phenoxyacetyl chloride
[0011] Add phenoxyacetic acid, thionyl chloride and DMF (N,N-dimethylformamide) to a reactor, and react at 40°C to 70°C to obtain phenoxyacetyl chloride;
[0012] (2) Preparation of penicillin V acid
[0013] Add acetone, water and 6-APA to a reactor, and dropwise add triethylamine at 0°C to 20°C until 6-APA is completely dissolved; then dropwise add a sodium hydroxide solution at 0°C to 10°C, and at the same time dropwise add the phenoxyacetyl chloride obtained in the above step (1) to make the pH 5.5 to 7.5 for condensation reaction. After the addition is completed, continue to keep the temperature for reaction; after the reaction is completed, add water to the reaction solution, dropwise add dilute sulfuric acid for acidification, adjust its pH to 1 to 3 to make penicillin V acid crystallize out, keep the temperature for crystal cultivation, filter, wash and dry to obtain penicillin V acid solid;
[0014] (3) Preparation of penicillin V potassium
[0015] Dissolve the penicillin V acid obtained in the above step (2) in ethanol, and obtain a purified ethanol solution of penicillin V acid through decolorization with activated carbon; dissolve potassium acetate in water, and obtain a purified aqueous solution of potassium acetate through decolorization with activated carbon; dropwise add the purified aqueous solution of potassium acetate to the purified ethanol solution of penicillin V acid for salt formation reaction. After the addition is completed, cool for crystal cultivation, filter, wash and dry to obtain the finished product of penicillin V potassium.
[0016] Next, in combination withFigure 1 , Figure 1 is the process flow diagram of the preparation method of penicillin V potassium of the present invention, and the preparation method of penicillin V potassium of the present invention is described in more detail.
[0017] As Figure 1 shown, the preparation method of penicillin V potassium of the present invention includes the synthesis of phenoxyacetyl chloride, the preparation of penicillin V acid and the preparation of penicillin V potassium.
[0018] In the synthesis of phenoxyacetyl chloride in the step (1), phenoxyacetic acid, thionyl chloride and DMF (N,N-dimethylformamide) are added into a reactor, and the reaction is carried out at 40°C to 70°C to obtain phenoxyacetyl chloride;
[0019] More specifically, in the reaction, the molar ratio of phenoxyacetic acid to thionyl chloride can be 1:1 to 3, preferably 1:2 to 3, more preferably 1:2 to 2.5. The molar ratio of phenoxyacetic acid to DMF can be 1:0.01 to 1, preferably 1:0.01 to 0.1, more preferably 1:0.02 to 0.05.
[0020] In this reaction, the reaction temperature can be 40°C to 70°C, preferably 40°C to 60°C, more preferably 40°C to 50°C; the reaction time can be 0.5 to 5 h, preferably 1 to 3 h, more preferably 1 to 2 h.
[0021] In this reaction, adding DMF (N,N-dimethylformamide) can promote the reaction to occur.
[0022] After the reaction of phenoxyacetic acid and thionyl chloride is completed, vacuum distillation is carried out to remove the excess thionyl chloride until no distillate is obtained, and phenoxyacetyl chloride is obtained for standby.
[0023] In the preparation of penicillin V acid in the step (2), acetone, water and 6-APA are added into a reactor, and triethylamine is added dropwise at 0°C to 20°C until 6-APA is completely dissolved; then sodium hydroxide solution is added dropwise at 0°C to 10°C, and at the same time the phenoxyacetyl chloride obtained in the above step (1) is added dropwise to carry out a condensation reaction with a pH of 5.5 to 7.5. After the addition is completed, the reaction is continued under heat preservation; after the reaction is completed, water is added to the reaction solution, and dilute sulfuric acid is added dropwise for acidification to adjust its pH to 1 to 3, so that penicillin V acid crystallizes out, and the crystal is cultured under heat preservation, filtered, washed and dried to obtain solid penicillin V acid.
[0024] More specifically, in the reaction of 6-APA with phenoxyacetyl chloride, the molar ratio of 6-APA to phenoxyacetyl chloride can be 1:1 to 3, preferably 1:1 to 2, more preferably 1:1 to 1.5; the weight ratio of 6-APA to acetone can be 1:1 to 10, preferably 1:2 to 5; the weight ratio of 6-APA to water can be 1:1 to 7, preferably 1:1 to 3.5, more preferably 1:1 to 2.
[0025] Triethylamine is added dropwise to dissolve 6-APA, and the temperature is controlled at 0°C to 20°C, preferably 0°C to 10°C, more preferably 5°C to 10°C; the amount of triethylamine used for dissolution is generally such that the weight ratio of 6-APA to triethylamine is 1:0.1 to 5, preferably 1:0.1 to 3, more preferably 1:0.1 to 1.
[0026] The sodium hydroxide solution can be a 5wt% to 20wt% sodium hydroxide solution, preferably an 8wt% to 12wt% sodium hydroxide solution.
[0027] The sodium hydroxide solution is added dropwise at 0°C to 10°C, and at the same time, the phenoxyacetyl chloride obtained in the above step (1) is added dropwise. Specifically, for example, a peristaltic pump is used to control the dropping rate of the sodium hydroxide solution at 2 to 10 rpm, and at the same time, a dropping funnel is used to control the dropping of the phenoxyacetyl chloride obtained in the above step (1), so that the pH of the reaction solution is controlled at 5.5 to 7.5 during this process. The dropping time is generally controlled at 1 to 5 h. After the dropping is completed, the reaction is continued to be heated until the residual amount of 6-APA is less than 2 mg / ml, and the heating reaction time is generally controlled at 30 min to 1 h.
[0028] After the reaction is completed, water is added to the reaction solution, and the amount of water added can be such that the weight ratio of 6-APA to water is 1:1 to 14, preferably 1:1 to 7, more preferably 1:1 to 4.
[0029] The dilute sulfuric acid used for acidification crystallization can be a 10wt% to 30wt% dilute sulfuric acid, preferably a 15wt% to 25wt% dilute sulfuric acid.
[0030] In step (2), the yield of penicillin V acid can reach more than 94%, and the yield = (weight of penicillin V acid solid) / (weight of 6-APA * 1.62) × 100%, and the purity is more than 98%.
[0031] In the preparation of potassium penicillin V in the above step (3), the penicillin V acid obtained in the above step (2) is dissolved in ethanol, and the purified ethanol solution of penicillin V acid is obtained through decolorization with activated carbon; potassium acetate is dissolved in water, and the purified aqueous solution of potassium acetate is obtained through decolorization with activated carbon; the purified aqueous solution of potassium acetate is added dropwise to the purified ethanol solution of penicillin V acid for salt formation reaction. After the dropping is completed, the temperature is lowered for crystal cultivation, and then filtered, washed, and dried to obtain the finished product of potassium penicillin V.
[0032] Among them, the penicillin V acid obtained in the above step (2) is dissolved in ethanol, and the purified ethanol solution of penicillin V acid is obtained through decolorization with activated carbon. Penicillin V acid is dissolved in ethanol, and the dosage of ethanol is not limited as long as penicillin V acid can be dissolved. More specifically, relative to 1 g of penicillin V acid, the dosage of ethanol can be 3 - 10 ml, preferably 5 - 8 ml. Penicillin V acid is dissolved in ethanol, and the temperature is controlled at 20°C - 60°C, preferably 20°C - 50°C, more preferably 30°C - 50°C. The purified ethanol solution of penicillin V acid is obtained through decolorization with activated carbon. The dosage of activated carbon is generally 0.1% - 0.9% of the weight of penicillin V acid, preferably 0.3% - 0.5%.
[0033] Potassium acetate is dissolved in water, and the purified aqueous solution of potassium acetate is obtained through decolorization with activated carbon. Potassium acetate is dissolved in water, and the dosage of water is not limited as long as potassium acetate can be dissolved. More specifically, relative to 1 g of potassium acetate, the dosage of water can be 0.1 - 3 ml, preferably 0.1 - 2 ml. The purified aqueous solution of potassium acetate is obtained through decolorization with activated carbon. The dosage of activated carbon is generally 0.1% - 0.9% of the weight of potassium acetate, preferably 0.3% - 0.5%.
[0034] The purified aqueous solution of potassium acetate is dropped into the ethanol solution of purified penicillin V acid for salt formation reaction. In the salt formation reaction, the molar ratio of penicillin V acid to potassium acetate is 1:1 - 3, preferably 1:1 - 2, more preferably 1:1 - 1.5.
[0035] The temperature of the salt formation reaction is 20°C - 50°C, preferably 20°C - 40°C, more preferably 30°C - 40°C.
[0036] The temperature for cooling and crystal cultivation is 0°C - 15°C, preferably 0°C - 10°C, more preferably 0°C - 5°C.
[0037] The penicillin V potassium prepared by the present invention has a purity of over 99.0% and a yield of over 94%. Yield = (weight of penicillin V potassium) / (penicillin V acid * 1.11) × 100%.
[0038] Beneficial effects
[0039] The preparation method of penicillin V potassium provided by the present invention prepares penicillin V potassium by a chemical synthesis method. The process is simple, with few production raw materials, few impurities carried by the raw materials, low power consumption, few equipment used, and low production cost. It is a method that can effectively reduce costs and improve the quality of the finished product. Brief description of the drawings
[0040] Figure 1 It is the process flow chart of the preparation method of penicillin V potassium of the present invention. Detailed Embodiments
[0041] The preparation method of penicillin V potassium of the present invention will be further described in detail below through embodiments. The protection scope of the present invention is not limited to the following embodiments. These embodiments are listed only for illustrative purposes and do not limit the present invention in any way.
[0042] Example 1
[0043] (1) Synthesis of phenoxyacetyl chloride
[0044] Add 240 g (1.58 moles) of phenoxyacetic acid, 384 g (3.23 moles) of thionyl chloride, and 4.8 g of DMF into a reaction flask, heat up to 50 °C, and keep the reaction for 2 h. After the reaction is completed, distill thionyl chloride under reduced pressure until no distillate comes out. After distillation, about 280 g of phenoxyacetyl chloride is obtained.
[0045] (2) Preparation of penicillin V acid
[0046] Add 320 ml of acetone, 100 ml of purified water, and 80 g (0.37 mole) of 6-APA into a reactor, start stirring, cool down to 20 °C, and slowly dropwise add triethylamine until 6-APA is completely dissolved and clear. At this time, the amount of triethylamine added is 48 g; after dissolution and clarification, slowly dropwise add 192 g of 10 wt% sodium hydroxide solution using a peristaltic pump at a rate of 10 rpm, and at the same time dropwise add 72 g (0.42 mole) of the above-obtained phenoxyacetyl chloride using a dropping funnel. During this process, control the reaction temperature at 8 - 10 °C and the pH at 7.0 - 7.5; after the addition is complete, continue to keep the reaction for 1 h. At this time, detect that the residual amount of 6-APA is less than 2 mg / ml; after the heat preservation reaction is completed, add 200 ml of purified water, stir evenly, start to dropwise add 10 wt% dilute sulfuric acid to adjust the pH to 2.0, and use 200 ml of dilute sulfuric acid; after the acidification reaction is completed, keep the temperature for crystal cultivation for 1 h, filter, wash, and dry to obtain 123.12 g of penicillin V acid finished product, with a yield of 95%.
[0047] (3) Preparation of penicillin V potassium
[0048] At 35 °C, dissolve 100 g (0.285 mole) of the penicillin V acid obtained in the above step (2) in 800 ml of ethanol. After dissolution, add 0.4 g of activated carbon and stir for decolorization for 30 min. After filtration, a purified ethanol solution of penicillin V acid is obtained;
[0049] Dissolve 40 g (0.408 mole) of potassium acetate in 40 ml of purified water. After dissolution, add 0.15 g of activated carbon and stir for decolorization for 30 min. After filtration, a purified aqueous solution of potassium acetate is obtained;
[0050] At a temperature of 30°C - 33°C, a purified aqueous potassium acetate solution was dropped into a purified ethanol solution of penicillin V acid for a salt-forming reaction. After the dropping was completed, the temperature was lowered to about 9°C for crystal cultivation for 1 h, followed by filtration, washing, and drying to obtain 106.56 g of penicillin V potassium product. The yield was 96%. After HPLC detection, the purity of penicillin V potassium was 99.0% and the melting point was 199°C.
[0051] Example 2
[0052] (1) Synthesis of phenoxyacetyl chloride
[0053] 240 g (1.58 moles) of phenoxyacetic acid, 384 g (3.23 moles) of thionyl chloride, and 4.8 g of DMF were added to a reaction flask, and the temperature was raised to 50°C and the reaction was maintained for 2 h. After the reaction was completed, thionyl chloride was distilled under reduced pressure until no more distillate came out. After distillation, about 280 g of phenoxyacetyl chloride was obtained.
[0054] (2) Preparation of penicillin V acid
[0055] 320 ml of acetone, 100 ml of purified water, and 80 g (0.37 moles) of 6-APA were added to a reactor, and stirring was started. The temperature was lowered to 15°C, and triethylamine was slowly dropped into it until 6-APA was completely dissolved and clear. At this time, the amount of triethylamine added was 48 g. After dissolution and clarification, 192 g of 10 wt% sodium hydroxide solution was dropped using a peristaltic pump at a rate of 5 rpm, and at the same time, 72 g (0.42 moles) of the above-obtained phenoxyacetyl chloride was dropped using a dropping funnel. During this process, the reaction temperature was controlled at 5 - 8°C and the pH was 7.0 - 7.5. After the addition was completed, the reaction was continued to be maintained for 45 min. At this time, the residual amount of 6-APA was detected to be less than 2 mg / ml. After the holding reaction was completed, 200 ml of purified water was added, stirred evenly, and 10 wt% dilute sulfuric acid was started to be dropped to adjust the pH to 2.0, using 200 ml of dilute sulfuric acid. After the acidification reaction was completed, it was kept for crystal cultivation for 1 h, filtered, washed, and dried to obtain 124.42 g of penicillin V acid product with a yield of 96%.
[0056] (3) Preparation of penicillin V potassium
[0057] At 35°C, 100 g (0.285 moles) of penicillin V acid obtained in the above step (2) was dissolved in 800 ml of ethanol. After dissolution, 0.4 g of activated carbon was added and stirred for decolorization for 30 min. After filtration, a purified ethanol solution of penicillin V acid was obtained;
[0058] 40 g of potassium acetate (0.408 moles) was dissolved in 40 ml of purified water. After dissolution, 0.15 g of activated carbon was added and stirred for decolorization for 30 min. After filtration, a purified aqueous potassium acetate solution was obtained;
[0059] At a temperature of 30°C - 33°C, a purified aqueous potassium acetate solution was dropped into a purified ethanol solution of penicillin V acid for a salt-forming reaction. After the dropping was completed, the temperature was lowered to about 9°C for crystal cultivation for 1 h, followed by filtration, washing, and drying to obtain 104.34 g of penicillin V potassium product. The yield was 94%. After HPLC detection, the purity of penicillin V potassium was 99.2%, and the melting point was 199°C.
[0060] Example 3
[0061] (1) Synthesis of phenoxyacetyl chloride
[0062] 240 g (1.58 moles) of phenoxyacetic acid, 384 g (3.23 moles) of thionyl chloride, and 4.8 g of DMF were added to a reaction flask, and the temperature was raised to 50°C and kept for reaction for 2 h. After the reaction was completed, thionyl chloride was distilled under reduced pressure until no distillate came out. After distillation, about 280 g of phenoxyacetyl chloride was obtained.
[0063] (2) Preparation of penicillin V acid
[0064] 320 ml of acetone, 100 ml of purified water, and 80 g (0.37 mole) of 6-APA were added to a reactor, and stirring was started. The temperature was lowered to 10°C, and triethylamine was slowly dropped into it until 6-APA was completely dissolved and clear. At this time, the amount of triethylamine added was 48 g. After dissolution and clarification, 192 g of 10 wt% sodium hydroxide solution was dropped using a peristaltic pump at a rate of 2 rpm, and at the same time, 72 g (0.42 mole) of the above-obtained phenoxyacetyl chloride was dropped using a dropping funnel. During this process, the reaction temperature was controlled at 0 - 5°C and the pH was 7.0 - 7.5. After the addition was completed, the reaction was continued to be kept for 30 min. At this time, the residual amount of 6-APA was detected to be less than 2 mg / ml. After the holding reaction was completed, 200 ml of purified water was added, stirred evenly, and 10 wt% dilute sulfuric acid was started to be dropped to adjust the pH to 2.0, and 200 ml of dilute sulfuric acid was used up. After the acidification reaction was completed, it was kept for crystal cultivation for 1 h, filtered, washed, and dried to obtain 125.32 g of penicillin V acid product, and the yield was 96.7%.
[0065] (3) Preparation of penicillin V potassium
[0066] At 35°C, 100 g (0.285 mole) of penicillin V acid obtained in the above step (2) was dissolved in 800 ml of ethanol. After dissolution, 0.4 g of activated carbon was added, and stirring and decolorization were carried out for 30 min. After filtration, a purified ethanol solution of penicillin V acid was obtained;
[0067] 40 g of potassium acetate (0.408 mole) was dissolved in 40 ml of purified water. After dissolution, 0.15 g of activated carbon was added, and stirring and decolorization were carried out for 30 min. After filtration, a purified aqueous potassium acetate solution was obtained;
[0068] At a temperature of 30°C - 33°C, a purified aqueous solution of potassium acetate was added dropwise to a purified ethanol solution of penicillin V acid for a salt formation reaction. After the addition was completed, the temperature was lowered to about 9°C for crystallization for 1 h, followed by filtration, washing, and drying to obtain 105.45 g of penicillin V potassium solid. The yield was 95%. After HPLC detection, the purity of penicillin V potassium was 99.5% and the melting point was 199°C.
Claims
1. A preparation method of phenoxymethylpenicillin potassium, comprising the following steps: (1) Synthesis of phenoxyacetyl chloride Add phenoxyacetic acid, thionyl chloride and DMF (N,N-dimethylformamide) into a reactor, and react at 40°C to 70°C to obtain phenoxyacetyl chloride; (2) Preparation of penicillin V acid Add acetone, water and 6-APA into a reactor, and dropwise add triethylamine at 0°C to 20°C until 6-APA is completely dissolved; then dropwise add sodium hydroxide solution at 0°C to 10°C, and at the same time dropwise add the phenoxyacetyl chloride obtained in the above step (1) to make the pH 5.5 to 7.5 for condensation reaction. After the addition is completed, continue to keep the temperature for reaction; after the reaction is completed, add water to the reaction solution, dropwise add dilute sulfuric acid for acidification, adjust its pH to 1 to 3 to make penicillin V acid crystallize out, keep the temperature for crystal cultivation, filter, wash and dry to obtain solid penicillin V acid; (3) Preparation of penicillin V potassium Dissolve the penicillin V acid obtained in the above step (2) in ethanol, and decolorize with activated carbon to obtain a purified ethanol solution of penicillin V acid; dissolve potassium acetate in water, and decolorize with activated carbon to obtain a purified aqueous solution of potassium acetate; dropwise add the purified aqueous solution of potassium acetate into the purified ethanol solution of penicillin V acid for salt formation reaction. After the addition is completed, cool down for crystal cultivation, filter, wash and dry to obtain the finished product of penicillin V potassium.
2. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the synthesis of phenoxyacetyl chloride in the above step (1), the molar ratio of phenoxyacetic acid to thionyl chloride is 1:1 to 3, and the molar ratio of phenoxyacetic acid to DMF is 1:0.01 to 1; the reaction temperature is 40°C to 60°C, and the reaction time is 0.5 to 5 h.
3. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the synthesis of phenoxyacetyl chloride in the above step (1), after the reaction of phenoxyacetic acid and thionyl chloride is completed, carry out vacuum distillation to remove the excess thionyl chloride until no distillate comes out to obtain phenoxyacetyl chloride.
4. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the preparation of penicillin V acid in the above step (2), in the reaction of 6-APA and phenoxyacetyl chloride, the molar ratio of 6-APA to phenoxyacetyl chloride is 1:1 to 3.
5. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the preparation of penicillin V acid in the above step (2), add acetone, water and 6-APA into a reactor, and dropwise add triethylamine at 0°C to 20°C until 6-APA is completely dissolved, wherein the weight ratio of 6-APA to acetone is 1:1 to 10, and the weight ratio of 6-APA to water is 1:1 to 7.
6. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the preparation of penicillin V acid in the above step (2), use a peristaltic pump to control the dropping of the sodium hydroxide solution at a speed of 2 to 10 rpm, and at the same time use a dropping funnel to control the dropping of the phenoxyacetyl chloride obtained in the above step (1) to make the pH of the reaction solution 5.5 to 7.5 during this process, and control the addition time to 1 to 5 h. After the addition is completed, continue to keep the temperature for reaction until the residual amount of 6-APA is less than 2 mg / ml.
7. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the preparation of penicillin V acid in the above step (2), after the reaction is completed, add water to the reaction solution, and the amount of water added is such that the weight ratio of 6-APA to water is 1:1 to 14; the dilute sulfuric acid used for acidification crystallization is 10 wt% to 30 wt% dilute sulfuric acid.
8. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the preparation of penicillin V potassium in step (3), penicillin V acid is dissolved in ethanol. For 1 g of penicillin V acid, the amount of ethanol used is 3 - 10 ml, and the temperature is controlled at 20°C - 60°C; potassium acetate is dissolved in water. For 1 g of potassium acetate, the amount of water used is 0.1 - 3 ml.
9. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the preparation of penicillin V potassium in step (3), in the salt formation reaction, the molar ratio of penicillin V acid to potassium acetate is 1:1 - 3, the salt formation reaction temperature is 20°C - 50°C, and the temperature for cooling and crystal cultivation is 0°C - 15°C.
10. The preparation method of potassium penicillin V according to claim 1, characterized in that, in In the synthesis of phenoxyacetyl chloride in step (1), the molar ratio of phenoxyacetic acid to thionyl chloride is 1:1 - 3, and the molar ratio of phenoxyacetic acid to DMF is 1:0.01 - 1; the reaction temperature is 40°C - 60°C, and the reaction time is 0.5 - 5 h; after the reaction of phenoxyacetic acid and thionyl chloride is completed, vacuum distillation is carried out to remove the excess thionyl chloride until no distillate comes out to obtain phenoxyacetyl chloride; In the preparation of penicillin V acid in step (2), acetone, water and 6-APA are added to the reactor, and triethylamine is added dropwise at 0°C - 20°C until 6-APA is completely dissolved. The weight ratio of 6-APA to acetone is 1:1 - 10, and the weight ratio of 6-APA to water is 1:1 - 7; the dropping of the sodium hydroxide solution is controlled by a peristaltic pump at a speed of 2 - 10 rpm, and at the same time, the phenoxyacetyl chloride obtained in the above step (1) is added dropwise by a dropping funnel, so that the pH of the reaction solution is controlled at 5.5 - 7.5 during this process, and the addition time is controlled within 1 - 5 h. After the addition is completed, the reaction is continued to be heated until the residual amount of 6-APA is less than 2 mg / ml; after the reaction is completed, water is added to the reaction solution, and the amount of water added is such that the weight ratio of 6-APA to water is 1:1 - 14; the dilute sulfuric acid used for acidification and crystallization is 10 wt% - 30 wt% dilute sulfuric acid; in the reaction of 6-APA and phenoxyacetyl chloride, the molar ratio of 6-APA to phenoxyacetyl chloride is 1:1 - 3; In the preparation of penicillin V potassium in step (3), penicillin V acid is dissolved in ethanol. For 1 g of penicillin V acid, the amount of ethanol used is 3 - 10 ml, and the temperature is controlled at 20°C - 60°C; potassium acetate is dissolved in water. For 1 g of potassium acetate, the amount of water used is 0.1 - 3 ml; in the salt formation reaction, the molar ratio of penicillin V acid to potassium acetate is 1:1 - 3, the salt formation reaction temperature is 20°C - 50°C, and the temperature for cooling and crystal cultivation is 0°C - 15°C.