A new coupled crystallization method for preparing high-quality nafcillin sodium

Abstract

The present invention discloses a novel coupled crystallization method for preparing a superior grade of nafcillin sodium. The method comprises the following steps: adding crude nafcillin sodium, solvent I, and solvent II to a crystallizer, stirring to dissolve the crude product; adding solvent III at a constant temperature and rate, stirring to produce crystals, and growing the crystals. After growing the crystals, solvent III is added at a constant rate, the temperature is lowered, the product is filtered, and the resulting solid is dried to obtain the final product. The resulting product is white blocky or flaky crystals with a purity of up to 99.2% and a process yield of 81%. The resulting product maintains relatively stable physical and chemical properties after storage for 30 days at 30±5°C and 40±5% RH. The aqueous solution thereof is colorless, clear, and transparent, with an acidity of 5.77 to 6.23. The product has large particle size, making solid-liquid separation easy. The required equipment is simple, the processing scale is large, and the operation is simple. The product can be industrialized and has good technical and economic benefits and high industrial application value.

Description

Technical Field

[0001] The invention belongs to the technical fields of medicine and chemical industry, and particularly relates to a coupled crystallization refining method for a superior grade of nafcillin sodium. Background Art

[0002] Nafcillin sodium (CAS: 985-16-0), also known as ethoxynaphthyl penicillin, neopenicillin III, and trade name Unipen, was first developed by Wyeth Company in the United States. Its chemical name is (2S, 5R)-3,3-dimethyl-6-(2-ethoxy-1-naphthyl)-7-oxido-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt monohydrate, and its molecular formula is C 21 H 21 N2NaO5S·H2O, with a molecular weight of 454.49, is a white or off-white crystalline powder that is highly soluble in water and has a broad-spectrum antibacterial effect against both Gram-positive and Gram-negative bacteria. It is suitable for penicillin-resistant Staphylococcus aureus infections and other penicillin-sensitive bacterial infections, such as sepsis, endocarditis, empyema, liver abscess, pneumonia, and osteomyelitis. Its structural formula is shown below:

[0003]

[0004] The preparation of nafcillin sodium usually requires first synthesizing nafcillin acid, and then reacting it with a sodium compound to generate it. The preparation method includes using phenoxyacetyl chloride and 6-aminopenicillanic acid for reaction, or using nafcillin acid and sodium hydroxide for neutralization reaction. Specifically, 2-ethoxy-1-naphthoic acid, thionyl chloride and dimethylformamide are reacted with acyl chloride in dichloromethane, and then condensed with 6-APA at low temperature to obtain nafcillin acid, and then nafcillin sodium is prepared by coal dissolution method. The disadvantages of this method are that the reaction temperature is too high, and excessive thionyl chloride will affect the acyl chloride reaction, resulting in an increase in by-products. It is not easy to separate and purify during post-treatment, and the resulting nafcillin sodium product has poor crystallinity, purity, color, acidity, turbidity and stability.

[0005] Existing reports on the synthesis of nafcillin sodium, such as those in J. Chem. Soc., 1963: 491, J. Pharm. Sci. 1963, 52(8): 763, CN 101781315A, and CN 101456869B, all involve condensation reactions carried out in organic solvents. These organic solvents are expensive, highly volatile, and pose serious environmental risks. Furthermore, these steps only yield a crude nafcillin sodium product, which requires further refining to obtain the finished product. This results in cumbersome operations, low yields, and high costs. CN 101659670A and CN 101781315A report synthesizing nafcillin sodium using nafcillin acid, but the amount of acetone used as the solvent is too high (40-50 times the amount of nafcillin acid added), resulting in low production capacity, high manufacturing costs, and unsuitability for industrial production. Chinese patent (CN200810080292.9) uses 2-ethoxy-1-naphthoic acid as the starting material and produces nafcillin sodium through a four-step reaction process of chlorination, condensation, acidification, and alkalization. This process is long and complex, and the prepared nafcillin sodium exists in the form of an aqueous solution, which is not conducive to storage and transportation. Prolonged storage or high temperatures can easily lead to hydrolysis and destruction of the lactam ring, resulting in loss of antibacterial activity, affecting product quality. U.S. Patent (US3157639) discloses a method for salting nafcillin sodium. The salt is formed by dissolving nafcillin acid in an aqueous solution of sodium carbonate. After removing the aqueous solution by vacuum evaporation, the resulting solid is dissolved in a small amount of water and recrystallized by adding n-butanol. However, nafcillin sodium is unstable in aqueous solution, and the vacuum evaporation operation easily destroys the nafcillin sodium structure. Furthermore, the operation is complex, and the resulting product has low purity. A Chinese patent (CN106800565A) discloses a crystalline form of nafcillin sodium and its preparation method. The resulting product is not a new crystalline form of nafcillin sodium, but rather a crystal of an intermediate. A Chinese patent (CN201911039681.1) achieves the controlled preparation of single crystals or amorphous forms of nafcillin sodium through lyophilization. A Chinese patent (CN201910675307.4) discloses a novel nafcillin sodium injection. However, all of these products presuppose high-quality nafcillin sodium. However, to date, no method for refining and purifying superior nafcillin sodium has been reported. Summary of the Invention

[0006] In response to the above problems, the present invention discloses a dissolution-cooling coupled crystallization method for preparing a superior grade of nafcillin sodium from a crude nafcillin sodium product. The dissolution-cooling coupled crystallization technology disclosed in the present invention can obtain a superior grade of nafcillin sodium with high crystallinity, high purity and good stability. The method is simple to operate, low in cost and easy to industrialize.

[0007] The method for refining and crystallizing the superior grade of nafcillin sodium disclosed in the present invention has the following characteristic steps:

[0008] Step 1: adding crude nafcillin sodium and a mixed solvent of solvent I and solvent II into a crystallizer, controlling the temperature in the crystallizer, and starting a stirrer to dissolve the crude nafcillin sodium;

[0009] Step 2: Control the temperature in the crystallizer and keep it constant, control the stirring rate, add the dissolving agent III into the crystallizer at a constant rate, and grow the crystal for a period of time after the crystal is produced;

[0010] Step 3: After the crystal growth is completed, the solvent is continued to be added to the crystallizer at a constant rate; at the same time, the system is cooled to the final crystallization temperature at a certain rate to obtain a slurry;

[0011] Step 4: performing solid-liquid separation on the above slurry, drying, and finally obtaining a high-grade product of nafcillin sodium.

[0012] Preferably, any of the above is that the solvent I is at least one of methanol, water, ethyl acetate, and butyl acetate, and the solvent II is at least one of ethanol, isopropanol, acetone, and acetonitrile.

[0013] Preferably, in any of the above items, the mass ratio of solvent I to solvent II in step 1 is 1:2 to 1:4.

[0014] Preferably, in any of the above items, the mass ratio of the crude nafcillin sodium product in step 1 to the total mass of the mixed solvent is 1:1 to 1:2.

[0015] Any of the above is preferably that the temperature in the crystallizer in step 1 is 30-45°C.

[0016] Any of the above is preferably that the solvent III in step 2 is at least one of ethanol, isopropanol, acetone, and acetonitrile.

[0017] Preferably, in any of the above items, the flow rate of the dissolving agent III in step 2 is controlled to be 2-8 mL / min.

[0018] Preferably, in any of the above items, the ratio of the amount of the solvent III to the solvent I in step 2 is 1:20 to 1:30, and the water content of the solution in the crystallization system is about 3.5 to 5%.

[0019] Any of the above is preferably that the temperature in the crystallizer in step 2 is 30-45°C.

[0020] Preferably, in any of the above items, the crystal growing time in step 2 is 0.5 to 2 hours.

[0021] Preferably, in any of the above items, the flow rate of the dissolving agent III in step 3 is controlled to be 0.2-1.0 mL / min.

[0022] Preferably, in any of the above items, the ratio of the amount of the solvent III to the solvent I in step 3 is 1:10 to 1:20.

[0023] Preferably, in any of the above items, the cooling rate in step 3 is controlled at 0.1-0.25° C. / min.

[0024] Preferably, in any of the above items, the final cooling temperature in step 3 is controlled at 0-5°C.

[0025] Preferably, in any of the above items, the product is dried in step 4 by vacuum drying, with a vacuum degree of -0.06 to -0.1 MPa, a drying temperature of 40 to 50° C., and a drying time of 8 to 16 hours.

[0026] Advantages and beneficial effects of the present invention

[0027] Compared with the preparation method of nafcillin sodium reported in the literature, the present invention has significant advantages: the purity of the obtained product is ≥98%, and the yield is ≥81%. The white crystalline particles are easy to separate the solid and liquid (filter). The required equipment is simple, the processing scale is large, the operation is simple, and the preparation can be industrialized. The preparation has good technical and economic benefits and high industrial application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1a This is a microscope image of the morphology of the superior grade of nafcillin sodium prepared in Example 1 of the present invention;

[0029] Figure 1b This is a SEM image of the morphology of the superior grade of nafcillin sodium prepared in Example 1 of the present invention;

[0030] Figure 2 XRD patterns of the superior grade nafcillin sodium prepared in Examples 1 to 6 of the present invention;

[0031] Figure 3 TG / DSC graph of the superior grade of nafcillin sodium prepared in Example 1 of the present invention;

[0032] Figure 4 The Raman spectra of the superior grade of nafcillin sodium prepared in Examples 1 to 6 of the present invention;

[0033] Figure 5a The morphology and SEM image of the nafcillin sodium product prepared in Comparative Example 1;

[0034] Figure 5b The morphology and SEM image of the nafcillin sodium product prepared in Comparative Example 2;

[0035] Figure 5c The morphology and SEM image of the nafcillin sodium product prepared in Comparative Example 3;

[0036] Figure 6This is the XRD pattern of the nafcillin sodium product prepared in Comparative Examples 1-3. DETAILED DESCRIPTION

[0037] The present invention is described more clearly and completely through the following examples, but the examples described are only part of the embodiments of the present invention, not all of them. The examples are for helping to understand the present invention and should not be used to limit the scope of protection of the present invention.

[0038] Example 1:

[0039] A novel coupled crystallization method for preparing a superior grade of nafcillin sodium comprises the following steps:

[0040] Step 1: Dissolve 10.00 g of crude nafcillin sodium in a mixture of 10 mL of acetone and 3.3 mL of water at 35°C and stir until dissolved.

[0041] Step 2: Add 90 mL of acetone at a flow rate of 4 mL / min and grow the crystal for 0.5 h;

[0042] Step 3: Continue adding 30 mL of acetone to the crystallizer at a flow rate of 0.4 mL / min. At the same time, start the refrigeration program and control the system to cool down to 5°C at a cooling rate of 0.2°C / min to obtain crystal slurry;

[0043] Step 4: solid-liquid separation, drying the obtained solid at 45°C for 12 h to obtain 8.8 g of high-grade nafcillin sodium.

[0044] The final product is a block of white crystals with a morphology like Figure 1a and Figure 1b The X-ray powder diffraction spectrum is shown as Figure 2 As shown, the Raman spectrum is as follows Figure 4 The yield is 88%, the purity is 98.9%, and the aqueous solution is colorless, clear, and transparent with an acidity of 5.98.

[0045] Example 2:

[0046] A novel coupled crystallization method for preparing a superior grade of nafcillin sodium comprises the following steps:

[0047] Step 1: Dissolve 10.00 g of crude nafcillin sodium in a mixture of 10 mL of ethanol and 3.5 mL of water at 40°C and stir to dissolve.

[0048] Step 2: Add 90 mL of ethanol at a flow rate of 6 mL / min and grow the crystal for 1.0 h;

[0049] Step 3: Continue adding 30 mL of ethanol to the crystallizer at a flow rate of 0.2 mL / min. At the same time, start the refrigeration program and control the system to cool down to 3°C at a cooling rate of 0.19°C / min to obtain crystal slurry;

[0050] Step 4: solid-liquid separation, drying the obtained solid at 40°C for 8 h to obtain 8.6 g of high-grade nafcillin sodium.

[0051] The final product is a blocky white crystal, and the X-ray powder diffraction spectrum is as follows Figure 2 As shown, the Raman spectrum is as follows Figure 4 The yield is 86%, the purity is 98.7%, the aqueous solution is colorless, clear and transparent, and the acidity is 5.87.

[0052] Example 3:

[0053] A novel coupled crystallization method for preparing a superior grade of nafcillin sodium comprises the following steps:

[0054] Step 1: Dissolve 20.00 g of crude nafcillin sodium in a mixture of 20 mL of acetonitrile and 7 mL of ethyl acetate at 35°C and stir to dissolve.

[0055] Step 2: Add 180 mL of acetonitrile at a flow rate of 6 mL / min and grow the crystal for 2 h;

[0056] Step 3: Continue adding 60 mL of acetonitrile to the crystallizer at a flow rate of 0.6 mL / min. At the same time, start the refrigeration program and control the system to cool down to 5°C at a cooling rate of 0.15°C / min to obtain a crystal slurry;

[0057] Step 4: solid-liquid separation, drying the obtained solid at 45°C for 16 h to obtain 18.4 g of high-grade nafcillin sodium.

[0058] The final product is a blocky white crystal, and the X-ray powder diffraction spectrum is as follows Figure 2 As shown, the Raman spectrum is as follows Figure 4 The yield is 92%, the purity is 99.2%, the aqueous solution is colorless, clear and transparent, and the acidity is 6.19.

[0059] Example 4:

[0060] A novel coupled crystallization method for preparing a superior grade of nafcillin sodium comprises the following steps:

[0061] Step 1: Dissolve 10.00 g of crude nafcillin sodium in a mixture of 20 mL of isopropanol and 20 mL of butyl acetate at 30°C and stir to dissolve thoroughly.

[0062] Step 2: Add 380 mL of isopropanol at a flow rate of 8 mL / min and grow the crystal for 2 h;

[0063] Step 3: Continue adding 200 mL of isopropanol to the crystallizer at a flow rate of 1 mL / min. At the same time, start the refrigeration program and control the system to cool down to 5°C at a cooling rate of 0.1°C / min to obtain crystal slurry;

[0064] Step 4: solid-liquid separation, drying the obtained solid at 50°C for 10 h to obtain 8.1 g of high-grade nafcillin sodium.

[0065] The final product is a blocky white crystal, and the X-ray powder diffraction spectrum is as follows Figure 2 As shown, the Raman spectrum is as follows Figure 4 The yield is 81%, the purity is 99.1%, the aqueous solution is colorless, clear and transparent, and the acidity is 5.78.

[0066] Example 5:

[0067] A novel coupled crystallization method for preparing a superior grade of nafcillin sodium comprises the following steps:

[0068] Step 1: Dissolve 20.00 g of crude nafcillin sodium in a mixture of 20 mL of acetone and 10 mL of methanol at 45°C and stir to dissolve thoroughly.

[0069] Step 2: Add 200 mL of acetone at a flow rate of 6 mL / min and grow the crystal for 1.5 h;

[0070] Step 3: 100 mL of acetone was added to the crystallizer at a flow rate of 0.5 mL / min. At the same time, the refrigeration program was started and the system was cooled to 0°C at a cooling rate of 0.25°C / min to obtain a slurry.

[0071] Step 4: solid-liquid separation, drying the obtained solid at 40°C for 10 h to obtain 17.3 g of high-grade nafcillin sodium.

[0072] The final product is a blocky white crystal, and the X-ray powder diffraction spectrum is as follows Figure 2 As shown, the Raman spectrum is as follows Figure 4 The yield is 86.5%, the purity is 98.8%, the aqueous solution is colorless, clear and transparent, and the acidity is 5.85.

[0073] Example 6:

[0074] A novel coupled crystallization method for preparing a superior grade of nafcillin sodium comprises the following steps:

[0075] Step 1: Dissolve 20.00 g of crude nafcillin sodium in a mixture of 20 mL of acetonitrile and 6.6 mL of ethyl acetate at 40°C and stir to dissolve.

[0076] Step 2: Add 120 mL of acetonitrile at a flow rate of 4 mL / min and grow the crystal for 0.5 h;

[0077] Step 3: Continue adding 80 mL of acetonitrile to the crystallizer at a flow rate of 0.4 mL / min. At the same time, start the refrigeration program and control the system to cool down to 0°C at a rate of 0.2°C / min to obtain a crystal slurry;

[0078] Step 4: solid-liquid separation, drying the obtained solid at 45°C for 12 h to obtain 17.8 g of high-grade nafcillin sodium.

[0079] The final product is a blocky white crystal, and the X-ray powder diffraction spectrum is as follows Figure 2 As shown, the Raman spectrum is as follows Figure 4 The yield is 89%, the purity is 98.5%, the aqueous solution is colorless, clear and transparent, and the acidity is 6.23.

[0080] Chemical property tests were performed on the superior grade nafcillin sodium prepared in Examples 1-6 of the present invention.

[0081] 1) The chemical stability of the superior grade nafcillin sodium prepared in Examples 1-6 of the present invention was investigated. The product showed no changes in color, purity, or morphology during storage at 30±5°C and 40±5% RH for 30 days, indicating good chemical stability of the crystals. The results are shown in Table 1.

[0082] Table 1 Chemical stability study of nafcillin sodium of the present invention

[0083]

[0084] 2) After storage at 30±5°C and 40±5% RH for 5 to 30 days, the acidity and turbidity of the superior grade nafcillin sodium prepared in Examples 1-6 of the present invention were examined. The aqueous solutions of the products remained unchanged after the accelerated test, and the products were colorless, clear, and transparent with an acidity of 5.77 to 6.23, indicating good crystal stability. The results are shown in Table 2.

[0085] Table 2 Chemical stability study of nafcillin sodium of the present invention

[0086]

[0087] Comparative Example 1

[0088] The difference from Example 1 is that the solvent used in the dissolution process in step 1 is 13.3 mL of acetone. The final product has an irregular morphology, such as Figure 5a As shown; X-ray powder diffraction spectrum is shown Figure 6 The yield was 78%, the purity was 93.3%, the aqueous solution was light yellow, and the acidity was 5.68.

[0089] Comparative Example 2

[0090] The difference from Example 1 is that the solvent used in the dissolution process of step 1 is 13.3 mL of water. The final product has an irregular morphology, such as Figure 5b As shown; X-ray powder diffraction spectrum is shown Figure 6 The yield was 72.5%, the purity was 89.6%, the aqueous solution was light yellow, and the acidity was 5.76.

[0091] Comparative Example 3

[0092] The difference from Example 1 is that steps 2 and 3 are combined, 120 mL of acetone is added at a flow rate of 4 mL / min, and then the temperature is lowered to 5°C. The final product has an irregular morphology and is light yellow. Figure 5c As shown; X-ray powder diffraction spectrum is shown Figure 6 The yield was 77.8%, the purity was 91.6%, the aqueous solution was yellow, and the acidity was 5.58.

[0093] The product index in the comparative example is much lower than that in the embodiment. This is because the mixed solvent has a certain solubilizing effect on the impurities in the crude product, which prevents them from being separated out during the crystallization process, thereby improving the product purity. At the same time, the synergistic effect of the mixed solvent affects the crystal morphology and promotes the formation of bulk crystals. In addition, the addition method of the solvent can affect the growth rate of the crystal.

[0094] The present invention provides a method for preparing a superior grade of nafcillin sodium. Those skilled in the art can implement the method by drawing upon the disclosure herein and appropriately modifying raw materials, process parameters, and other aspects. The method and product of the present invention have been described using preferred embodiments. It is apparent to those skilled in the art that modifications, variations, and combinations of the methods and products described herein can be made without departing from the content, spirit, and scope of the present invention to implement the technology of the present invention. It is particularly important to note that all similar substitutions and modifications readily apparent to those skilled in the art are considered encompassed within the spirit, scope, and content of the present invention.

Claims

1. A novel coupled crystallization method for preparing a superior grade of nafcillin sodium, characterized in that: Here are the steps: Step 1: Add crude nafcillin sodium, solvent I, and solvent II to a crystallizer at 30 to 45° C. and stir to dissolve; the solvent I is at least one of methanol, water, ethyl acetate, and butyl acetate; the solvent II is at least one of ethanol, isopropanol, acetone, and acetonitrile; and the mass ratio of solvent I to solvent II is 1:2 to 1:4; Step 2: maintaining a constant temperature of 30 to 45°C, adding solvent III at a flow rate of 2 to 8 mL / min, wherein the ratio of solvent III to solvent I is 1:20 to 1:30, stirring to produce crystals, and growing the crystals for 0.5 to 2 hours. The solvent III is at least one of ethanol, isopropanol, acetone, and acetonitrile; Step 3: After the crystal growth is completed, add solvent III at a flow rate of 0.2 to 1.0 mL / min. The ratio of solvent III to solvent I is 1:10 to 1:

20. Cool at a cooling rate of 0.1 to 0.25 °C / min, and the final temperature is controlled at 0 to 5 °C. Step 4: Filter and dry the obtained solid to obtain the final product.

2. The novel coupled crystallization method for preparing a superior grade of nafcillin sodium according to claim 1, characterized in that: In step 1, the mass ratio of the crude nafcillin sodium to the total mass of the mixed solvent is 1:1 to 1:

2.

3. The novel coupled crystallization method for preparing a superior grade of nafcillin sodium according to claim 1, characterized in that: The water content of the solution in the crystallization system of step 2 is 3.5 to 5%.

4. The novel coupled crystallization method for preparing a superior grade of nafcillin sodium according to claim 1, characterized in that: The product is dried in step 4 by vacuum drying, with a vacuum degree of -0.06 to -0.1 MPa, a drying temperature of 40 to 50°C, and a drying time of 8 to 16 h.

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