A method for purifying a fluoroquinolone intermediate

Abstract

The present application relates to the technical field of drug intermediate purification, and discloses a method for purifying and preparing a flomoxef intermediate, which comprises the following steps: placing crude flomoxef intermediate to be purified in an ethyl acetate organic phase, adjusting the water content of the organic phase, pre-activating iodide, capturing sulfite, washing with thiosulfate, washing with buffer saline, concentrating and replacing, and sequentially performing anti-solvent crystallization treatment with methyl tert-butyl ether and n-heptane to obtain purified flomoxef intermediate. The present application can promote the transfer of halomethyl impurities to the water phase, inhibit the increase of sulfide oxidation impurities, and reduce the entrainment of residual inorganic ions and structural similar impurities, and is suitable for the industrial purification and preparation of flomoxef intermediate.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate purification technology, and in particular to a method for purifying and preparing a cephalosporin intermediate. Background Technology

[0002] Fluoxetine belongs to the class of oxocephalosporin antibiotics. Its key intermediates typically contain structural units such as an oxocephalosporin nucleus, sulfur-containing substituents, methoxy-substituted structures, and carboxyl protecting groups. These intermediates contain functional groups that are sensitive to acids, bases, moisture, oxidizing components, and metal ions, and are prone to generating structurally similar impurities during synthesis and post-processing. Common impurities in the crude product include residual halomethyl oxocephalosporin impurities, thioether oxidation impurities, free thiols or thiolate impurities, and other polar or weakly polar impurities. These impurities are structurally similar to the target intermediates, and some exhibit similar solubility behaviors in conventional organic solvent systems. Therefore, it is difficult to effectively control halomethyl impurities, oxidation impurities, and residual inorganic ions simultaneously using only ordinary water washing, salt washing, or single recrystallization treatment.

[0003] In the purification of cephalosporin intermediates, halomethyl impurities exhibit certain reactivity, but their residues in the organic phase are not easily removed directly by ordinary washing. If a one-time mixing process is used, adding iodides, sulfites, and other components simultaneously to the system can easily lead to non-selective consumption between aqueous reaction components and may also increase the contact time between the target intermediate and inorganic reaction components, thus affecting impurity conversion efficiency and product stability. Without a proper pre-activation and capture sequence, halomethyl impurities are difficult to fully convert into sulfonate conversion products that easily enter the aqueous phase, and residues may still appear during subsequent crystallization.

[0004] The thioether structure in these intermediates is also susceptible to oxidation by trace metal ions, peroxides in the solvent, and residual iodine-related components, forming thioether oxidation impurities. Conventional purification processes typically focus on the crystallization yield and appearance of the target product, with insufficient control over the correlation between metal ions, residual iodine-related components, peroxide sources, and washing endpoints during aqueous phase treatment. If metal ions or residual active components are not controlled before concentration and crystallization, thioether oxidation impurities may continue to increase in subsequent operations, leading to an increase in total related substances.

[0005] Furthermore, the purification of cephalosporin intermediates involves multiple liquid-liquid phase separation and antisolvent crystallization processes. The moisture content of the organic phase, salt concentration, buffer pH, and washing endpoint all affect phase separation, inorganic ion residue, and loss of the target intermediate. Using only a fixed number of washes as the endpoint may result in underwashing or overwashing. Underwashing leads to the residue of inorganic components such as iodide ions, sulfite, and thiosulfate; overwashing may increase the loss of the target intermediate or introduce additional moisture, affecting subsequent concentration and crystallization stability.

[0006] The crystallization step also affects the final purification effect. When a single antisolvent is added rapidly or the order of addition is changed, the supersaturation of the system changes quickly, easily leading to impurity co-precipitation, mother liquor entrainment, or high residual solvent levels in the filter cake. For crude fluorocephalosporin intermediates with similar structures and numerous impurities, conventional antisolvent crystallization alone is insufficient to control halomethyl impurities, thioether oxide impurities, total related substances, and residual solvents. Therefore, it is necessary to establish a purification and preparation method for fluorocephalosporin intermediates that combines reaction extraction, removal of residual active components, washing endpoint control, and sequential antisolvent crystallization. Summary of the Invention

[0007] The purpose of this invention is to provide a method for purifying and preparing fluorocephalosporin intermediates, so as to improve the problem that it is difficult to synergistically control halogenated methyl impurities, thioether oxide impurities, residual inorganic ions and structurally similar impurities in crude fluorocephalosporin intermediates.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] This invention provides a method for purifying and preparing an intermediate of fluorocephalosporin, comprising the following steps:

[0010] (1) Dissolve or disperse the crude intermediate of fluorocephalosporin to be purified in ethyl acetate to obtain an organic phase containing the target fluorocephalosporin intermediate, and adjust the moisture content of the organic phase;

[0011] (2) The organic phase obtained in step (1) is contacted with an iodide pre-activation solution containing iodide and disodium ethylenediaminetetraacetate to perform iodide pre-activation treatment. After standing and separating the layers, the aqueous phase is removed.

[0012] (3) Contact the organic phase obtained in step (2) with a sulfite capturing solution containing sulfite, iodide and disodium ethylenediaminetetraacetate to carry out sulfite capturing treatment, and separate the aqueous phase after standing and separating the layers.

[0013] (4) Contact the organic phase obtained in step (3) with the terminating washing solution containing thiosulfate to perform terminating washing, and separate the aqueous phase after standing and separating the layers.

[0014] (5) The organic phase obtained in step (4) is washed with buffer brine, then concentrated under reduced pressure and replaced with ethyl acetate solvent to obtain ethyl acetate concentrate, and isopropanol is added to the ethyl acetate concentrate to obtain the solution to be crystallized;

[0015] (6) Methyl tert-butyl ether is added to the crystallization solution obtained in step (5) to induce nucleation, seed crystals are added to grow crystals, and then n-heptane is added to crystallize. After solid-liquid separation, washing and drying, the purified intermediate of fluorocephalosporin is obtained.

[0016] By employing the above technical solution, the crude intermediate of fluorocephalosporin to be purified first enters the ethyl acetate organic phase. The target fluorocephalosporin intermediate is mainly retained in the organic phase, while water-soluble salts, some polar impurities, and easily transmissible components are separated through aqueous phase treatment. Adjusting the moisture content of the organic phase can control the interfacial state between the organic and aqueous phases, ensuring sufficient contact between the subsequent iodide pre-activation solution and sulfite capture solution and the halomethyl impurities in the organic phase, while reducing the impact of emulsification and phase separation delays on the reaction extraction efficiency.

[0017] In iodide pre-activation treatment, halomethyl impurities can be represented by R-CH2-X, where R represents the structural fragment related to the oxocephalosporin intermediate, and X represents the halogen leaving group. Upon contact with halomethyl impurities, halogen exchange or leaving group activation can occur, transforming the halomethyl impurities into an activated intermediate state more readily attacked by sulfite ions. The reaction process can be represented as follows:

[0018] R-CH2-X+I - →R-CH2-I+X - ;

[0019] The pre-activated halomethyl impurities undergo further nucleophilic substitution reactions with sulfite ions during sulfite capture treatment, generating highly water-soluble sulfonate conversion products. The reaction process can be represented as follows:

[0020] R-CH2-I+SO3 2- →R-CH2-SO3 - +I - ;

[0021] Or it can be expressed as:

[0022] R-CH2-X+SO3 2- →R-CH2-SO3 - +X - ;

[0023] Thus, halomethyl impurities originally remaining in the organic phase are transformed into water-soluble sulfonate conversion products after stepwise pre-activation and capture treatment, and then separated with the aqueous phase. The stepwise execution of iodide pre-activation and sulfite capture separates the pre-activation process involving iodide ions from the capture process involving sulfite ions in time sequence, which helps to reduce non-selective contact between iodide ions, sulfite ions, and target intermediates, and reduces inorganic salt entrainment and the increase of side reactions.

[0024] Disodium EDTA is used as a metal complexing component in iodide pre-activation solutions and sulfite capture solutions. The intermediate molecule of cephalosporin contains a thioether structure, which is easily oxidized in the presence of trace metal ions to form thioether oxide impurities. Disodium EDTA can complex trace metal ions such as iron, copper, and titanium, reducing their promoting effect on the thioether oxidation process, thereby inhibiting the growth of thioether oxide impurities during aqueous phase treatment, concentration, and crystallization.

[0025] Thiosulfate-termining washing solution is used for cleaning the organic phase after capture treatment. Thiosulfate reacts with residual iodine-related components, reducing their content in the organic phase and mitigating their adverse effects on thioether structures and other sensitive groups during subsequent concentration, displacement, and crystallization processes. The reaction process can be represented as follows:

[0026] I₂ + 2S₂O₃ 2 -→2I - +S4O6 2- ;

[0027] This termination washing step can reduce the impact of residual active iodine components and inorganic salt entrainment on the quality of subsequent products.

[0028] The organic phase, after termination washing, is further washed with buffered brine to allow residual iodide ions, sulfite ions, thiosulfate ions, and other water-soluble inorganic components to transfer further into the aqueous phase. pH control of the buffered brine helps maintain the stability of the target cephalosporin intermediate and related impurities during treatment. Changes in conductivity can reflect the degree of reduction of residual inorganic ions in the washing aqueous phase, thereby improving the controllability of washing endpoint determination.

[0029] Concentration and ethyl acetate solvent displacement are used to adjust the concentration of the target fluorocephalosporin intermediate in the ethyl acetate system and reduce residual water and low-boiling impurities introduced by the previous aqueous phase treatment. Adding isopropanol to the ethyl acetate concentrate improves the solubility of the target fluorocephalosporin intermediate in the solution before crystallization, providing a stable system for subsequent sequential antisolvent crystallization.

[0030] In the crystallization step, methyl tert-butyl ether is added first to gradually establish supersaturation and induce nucleation. After turbidity appears in the system, seed crystals are added to grow crystals, controlling the number of crystals and the growth process on the crystal surface. Subsequently, n-heptane is added to promote the continued precipitation of the target cephalosporin intermediate. The order of adding methyl tert-butyl ether first and then n-heptane separates the nucleation and crystallization stages, which helps reduce the entrainment of structurally similar impurities, halomethyl impurities, and residual solvents in the filter cake, improving crystallization selectivity and the quality of the dried product.

[0031] Preferably, in step (1), the concentration of the target cephalosporin intermediate in the organic phase is 90-140 g / L; before adjusting the moisture content, the organic phase is washed with an acetic acid / sodium acetate buffer solution, the pH of which is 5.2-5.7 and the sodium chloride concentration is 10-16 wt%; the moisture content of the organic phase is adjusted to 0.35-1.0 wt%.

[0032] By adopting the above technical solution, the concentration of the target cephalosporin intermediate in ethyl acetate is within a range suitable for liquid-liquid contact and subsequent concentration and crystallization; buffer brine washing can reduce water-soluble impurities in the crude product system in advance; adjusting the organic phase moisture to the above range is beneficial to maintaining the interfacial state when the organic phase and the aqueous phase are in contact, and improving the stability of subsequent stepwise reaction extraction.

[0033] Preferably, in step (2), the iodide is potassium iodide; the iodide pre-activation solution also contains sodium chloride and an acetic acid / sodium acetate buffer system; in the iodide pre-activation solution, the sodium chloride mass concentration is 14-18 wt%, the amount of potassium iodide is 0.003-0.012 equivalents of the target cephalosporin intermediate, the amount of disodium ethylenediaminetetraacetate is 0.002-0.006 equivalents of the target cephalosporin intermediate, and the pH of the aqueous phase is 5.2-5.6; the temperature of the iodide pre-activation treatment is 4-10℃, and the time is 10-25 min.

[0034] By employing the above technical solution, potassium iodide provides iodine ions to pre-activate halomethyl impurities, disodium ethylenediaminetetraacetate can complex trace metal ions, and sodium chloride is used to adjust the ionic strength of the aqueous phase and reduce the loss of the target fluorocephalosporin intermediate into the aqueous phase. By controlling the pH, temperature, and treatment time of the pre-activation solution within the aforementioned ranges, both the activation of halomethyl impurities and the stability of the target fluorocephalosporin intermediate can be achieved.

[0035] Preferably, in step (3), the sulfite is sodium sulfite, and the iodide is potassium iodide; the sulfite capturing solution also contains sodium chloride and an acetic acid / sodium acetate buffer system; in the sulfite capturing solution, the sodium chloride mass concentration is 10-15 wt%, the amount of sodium sulfite is 0.08-0.14 equivalents of the target cephalosporin intermediate, the amount of potassium iodide is 0.001-0.004 equivalents of the target cephalosporin intermediate, the amount of disodium ethylenediaminetetraacetate is 0.002-0.004 equivalents of the target cephalosporin intermediate, and the pH of the aqueous phase is 5.8-6.2; the temperature of the sulfite capturing treatment is 6-10℃, and the time is 40-70 min.

[0036] By employing the above technical solution, sulfite ions can undergo nucleophilic substitution reactions with pre-activated halomethyl impurities to generate water-soluble sulfonate conversion products. The retention of a small amount of iodide in the capture solution helps maintain the continuity between the activation and capture of halomethyl impurities. Disodium ethylenediaminetetraacetate continues to complex trace metal ions, reducing the increase of thioether oxide impurities during the capture process. Sulfite ions exhibit corresponding capture ability when the pH of the capture solution is between 5.8 and 6.2, while simultaneously reducing the impact of strong acid or strong alkaline conditions on the structural stability of the fluorocephalosporin intermediate.

[0037] Preferably, in step (4), the thiosulfate is sodium thiosulfate; the terminating wash solution also contains sodium chloride and an acetic acid / sodium acetate buffer system; in the terminating wash solution, the sodium chloride mass concentration is 10-16 wt%, the amount of sodium thiosulfate is 0.010-0.025 equivalents of the target cephalosporin intermediate, and the pH of the aqueous phase is 5.2-5.6; the terminating wash temperature is 4-10℃, and the time is 8-20 min.

[0038] By employing the above technical solution, sodium thiosulfate can remove residual iodine-related active components after capture treatment, thus terminating the reaction extraction process before subsequent washing, concentration, and crystallization. The sodium chloride and buffer system in the termination washing solution help maintain phase separation and aqueous phase pH, allowing residual inorganic components to enter the aqueous phase while reducing the loss of the target fluorocephalosporin intermediate.

[0039] Preferably, in step (5), the buffer brine is an acetic acid / sodium acetate buffer brine with a pH of 5.2 to 5.8 and a sodium chloride mass concentration of 10 to 15 wt%; the number of washing cycles is 2 to 3; the pH of the aqueous phase after the last wash is 5.2 to 5.8, and the difference between the conductivity of the aqueous phase after the last wash and the conductivity of the blank buffer brine in the same batch is not greater than 10% of the conductivity of the blank buffer brine in the same batch; the moisture content of the organic phase after washing is not higher than 0.5 wt%.

[0040] By employing the above technical solution, buffer brine washing can further reduce residual iodide ions, sulfite ions, thiosulfate ions, and other water-soluble components in the organic phase. Using the difference between the pH and conductivity of the final wash phase as the washing endpoint reflects the reduction in residual inorganic salts in the organic phase, reducing the problem of insufficient or excessive washing caused by a fixed number of washes. Controlling the moisture content of the organic phase after washing to no more than 0.5 wt% is beneficial for the stable progress of subsequent concentration, displacement, and crystallization processes.

[0041] Preferably, in step (5), the vacuum concentration is carried out at -0.095 to -0.080 MPa and 25 to 34°C; the concentration of the target cephalosporin intermediate in the ethyl acetate concentrate is 130 to 185 g / L; after adding isopropanol to the ethyl acetate concentrate, the volume ratio of ethyl acetate to isopropanol is 1:(0.10 to 0.22).

[0042] By employing the above technical solution, vacuum concentration can remove some solvent and residual water at lower temperatures, reducing the impact of heat on the fluorocephalosporin intermediate. Ethyl acetate solvent replacement stabilizes the main solvent composition in the system before crystallization, and the addition of isopropanol improves the solubility of the target fluorocephalosporin intermediate in the ethyl acetate concentrate, providing a suitable solvent environment for the sequential antisolvent crystallization of methyl tert-butyl ether and n-heptane.

[0043] Preferably, in step (6), based on the volume of ethyl acetate in the solution to be crystallized being 1.0V, the amount of methyl tert-butyl ether added is 0.30-0.70V, and the dropping time is 0.5-2.5h; after the system becomes turbid, seed crystals are added, the amount of seed crystals added is 0.10-0.40wt% of the theoretical mass of the target cephalosporin intermediate, and the crystal growth time is 70-120min; the amount of n-heptane added is 2.2-3.5V, and the dropping time is 1.5-5h.

[0044] By employing the above technical solution, and controlling the amount and dropping time of methyl tert-butyl ether within the aforementioned range, the solution to be crystallized can gradually reach a turbid state. After turbidity is achieved, seed crystals are added and crystals are nucleated, providing a stable nucleus base for crystal growth. Heptane is then added to allow the target cephalosporin intermediate to continue precipitating and complete the crystal growth process. This sequence allows the nucleation and crystallization processes to proceed in stages, which helps reduce impurity co-precipitation and solvent entrainment.

[0045] Preferably, in step (6), after adding n-heptane, the temperature is lowered to 0-5℃ at a rate of 0.10-0.20℃ / min and kept at this temperature for 2-4 hours; the filter cake obtained from solid-liquid separation is washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, wherein the volume ratio of ethyl acetate to n-heptane is 1:(3-5), and the amount of washing liquid used is 0.5-1.5 times the mass of the wet filter cake.

[0046] By adopting the above technical solutions, the control of cooling rate, final temperature, and holding time can enable the crystallization system to complete crystallization and crystal maturation, reducing impurity entrainment caused by rapid cooling. Washing the filter cake with a low-temperature ethyl acetate / n-heptane mixed solvent can remove residual mother liquor and some soluble impurities from the filter cake surface, while reducing the loss of the target cephalosporin intermediate during the washing process.

[0047] Preferably, the peroxide content of ethyl acetate, isopropanol, and methyl tert-butyl ether is not higher than 50 ppm; in the obtained purified fluorocephalosporin intermediate, the content of the main peak of the target fluorocephalosporin intermediate is not lower than 99.0%, the content of halomethyl impurities is not higher than 0.065%, the content of thioether oxide impurities is not higher than 0.070%, and the total related substances are not higher than 0.50%.

[0048] By employing the above technical solution, the low-peroxide solvent can reduce the oxidative impact of exogenous peroxides on the thioether structure, and together with the metal complexation control of disodium ethylenediaminetetraacetate, it can reduce the increase of thioether oxidation impurities. After the above stepwise reaction extraction, termination washing, buffer brine washing, and sequential antisolvent crystallization treatment, the content of the target intermediate, halomethyl impurities, thioether oxidation impurities, and total related substances in the obtained cephalosporin intermediate purified product can be synergistically controlled.

[0049] In summary, the present invention has at least one of the following beneficial technical effects:

[0050] 1. This invention employs a stepwise treatment of iodide pre-activation and sulfite capture, which first activates halomethyl impurities with iodide ions and then reacts with sulfite ions to generate water-soluble sulfonate conversion products, promoting the transfer of halomethyl impurities from the organic phase to the aqueous phase, thereby reducing the residual halomethyl impurities in the product.

[0051] 2. In this invention, disodium ethylenediaminetetraacetate is added to the iodide pre-activation solution and the sulfite capture solution to reduce the promoting effect of metal ions on the sulfide oxidation process by complexing trace metal ions, thereby inhibiting the increase of sulfide oxidation impurities.

[0052] 3. The present invention uses thiosulfate to terminate the washing process, which can reduce the impact of residual iodine-related components after capture treatment on the subsequent concentration and crystallization process, and is beneficial to controlling thioether oxidation impurities and residual inorganic ions.

[0053] 4. This invention uses pH and conductivity as control indicators for the washing endpoint of buffer brine, so that the washing state of residual inorganic ions in the organic phase can be controlled by the process, reducing the entrainment of inorganic salts caused by insufficient washing.

[0054] 5. The present invention employs a sequential antisolvent crystallization method, which first induces nucleation with methyl tert-butyl ether, then seed crystals, and finally crystallizes with n-heptane. This allows the nucleation and crystallization processes to proceed in stages, which helps reduce co-extrusion of impurities and solvent entrainment in the filter cake, thereby improving the quality stability of the purified cephalosporin intermediate. Attached Figure Description

[0055] Figure 1 These are the full HPLC spectra of the organic phase sample before pre-activation and the organic phase sample after sulfite capture in Example 1 of this invention.

[0056] Figure 2 This is a partial magnified HPLC image of the halomethyl impurity peaks in Example 1 and the comparative sample of Test Example 1 of this invention;

[0057] Figure 3 This is the LC-MS extracted ion current spectrum of the aqueous sulfonate conversion product in Test Example 1 of this invention;

[0058] Figure 4 These are comparative spectra of fractional reaction extraction and one-time mixing treatment in Test Example 2 of the present invention; wherein, (a) is a partial HPLC spectrum of halomethyl impurity peaks in sample S1 and sample D2; (b) is an LC-MS extraction ion current spectrum of sulfonate conversion products in the aqueous phase of sulfite capture in Example 1 and the aqueous phase of one-time mixing treatment in Comparative Example 2. Detailed Implementation

[0059] The present invention will be further described below with reference to embodiments and comparative examples, but the scope of protection of the present invention is not limited to the following embodiments. Any equivalent substitutions, conventional adjustments, or selections within the parameter range made by those skilled in the art based on the disclosure of the present invention without departing from the technical concept of the present invention shall fall within the scope of protection of the present invention.

[0060] Unless otherwise stated, "parts" in the following examples and comparative examples refer to parts by mass, and "equivalent" refers to the molar amount of the target cephalosporin intermediate in the crude cephalosporin intermediate to be purified; temperature is in °C, pressure is in MPa, concentration is in g / L, mol / L, wt% or vol%, and volume ratio is the volume ratio under the same temperature conditions. In the following examples and comparative examples, pH refers to the pH of the aqueous phase; water content was determined by the Karl Fischer method, and conductivity was determined by a conductivity meter; in HPLC analysis, the content of the target cephalosporin intermediate was calculated using the external standard method, and the content of halomethyl impurities, thioether oxide impurities, other largest single impurities, and total related substances was calculated using the area normalization method; unless otherwise specified, the content of the target cephalosporin intermediate and the content of total related substances are not to be interpreted as additive.

[0061] The main raw materials and reagents used in the following examples and comparative examples are described below. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0062] The crude intermediate of fluorocephalosporin is a crude intermediate containing an oxycephalosporin nucleus, a 7-position difluoromethylthioacetamide group, a 7-position methoxy group, a 3-position tetrazolium thiomethyl substituent, and a carboxyl protecting group. It appears as a white to pale yellow solid or an organic phase concentrate containing this intermediate. This crude product may contain residual oxycephalosporin impurities of halomethyl groups, thioether oxidation impurities, free thiols or thiolates, and structurally similar impurities. This crude intermediate of fluorosporin is used as the purification target in this invention.

[0063] Potassium iodide, CAS No. 7681-11-0, molecular formula KI, is used as a source of iodide ions. Sodium sulfite, CAS No. 7757-83-7, molecular formula Na₂SO₃, is used as a source of sulfite ions. Sodium thiosulfate, CAS No. 7772-98-7, molecular formula Na₂S₂O₃; sodium thiosulfate pentahydrate, CAS No. 10102-17-7, molecular formula Na₂S₂O₃·5H₂O, is used as a source of thiosulfate ions; when using sodium thiosulfate pentahydrate, it should be converted according to the effective amount of anhydrous sodium thiosulfate.

[0064] Disodium ethylenediaminetetraacetate, CAS No. 139-33-3, molecular formula C 10 H 14 N₂Na₂O₈; disodium ethylenediaminetetraacetate dihydrate, CAS No. 6381-92-6, molecular formula C₂Na₂O₈ 10 H 14 N2Na2O8·2H2O is used as a metal complexing agent; when using disodium ethylenediaminetetraacetate dihydrate, it is calculated based on the effective amount of anhydrous disodium ethylenediaminetetraacetate.

[0065] The seed crystals are solid intermediates with the same chemical composition as the target cephalosporin intermediate to be purified. They are obtained from a previous batch of qualified intermediates after drying and sieving. Before use, the seed crystals are vacuum dried at 25–35°C, sieved to a mesh size of 80–200 mesh, and the moisture content is controlled to be no more than 1.0 wt%.

[0066] Example 1:

[0067] This embodiment provides a method for purifying and preparing an intermediate of fluorocephalosporin, including the following steps:

[0068] (1) Take the crude intermediate of cephalosporin, calculate the content of the target cephalosporin intermediate according to the HPLC external standard method, add ethyl acetate with a peroxide content not exceeding 50 ppm, and prepare 1.0 L of organic phase with a target intermediate concentration of 120 g / L. Cool the organic phase to 8℃, add 300 mL of acetic acid / sodium acetate buffer solution with pH 5.5 and sodium chloride mass concentration of 12 wt%, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, stir for 10 min, let stand for 20 min, and separate the aqueous phase. Detect the moisture content of the organic phase and adjust the moisture content of the organic phase to 0.7 wt%; when the moisture content of the organic phase is lower than 0.7 wt%, add an appropriate amount of acetic acid / sodium acetate buffer solution with pH 5.5, stir and let stand to separate the layers; when the moisture content of the organic phase is higher than 0.7 wt%, dehydrate under reduced pressure for a short time at 20~30℃ and -0.095~-0.06 MPa.

[0069] (2) Add 350 mL of iodide pre-activation solution to the above organic phase. In the iodide pre-activation solution, the sodium chloride mass concentration is 17 wt%, the amount of potassium iodide is 0.008 equivalents of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.004 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 5.4. After addition, stir at 6 °C for 18 min, let stand for 20 min, and separate the aqueous phase.

[0070] (3) Add 500 mL of sulfite capture solution to the obtained organic phase. In the sulfite capture solution, the sodium chloride mass concentration is 14 wt%, the amount of sodium sulfite is 0.10 equivalent of the target intermediate molar amount, the amount of potassium iodide is 0.003 equivalent of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.003 equivalent of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 6.0. After addition, stir at 9℃ for 50 min. During stirring, use an aqueous solution of acetic acid or sodium acetate to control the pH of the aqueous phase at 5.8-6.2. Let stand for 20 min, and then separate the aqueous phase.

[0071] (4) Add 300 mL of thiosulfate termination washing solution to the obtained organic phase. The thiosulfate termination washing solution contains 14 wt% sodium chloride, 0.015 equivalents of the target intermediate molar amount of sodium thiosulfate, a total concentration of acetic acid and sodium acetate of 0.10 mol / L, and a pH of 5.5 in the aqueous phase. After addition, stir at 8 °C for 12 min, let stand for 20 min, and then separate the aqueous phase.

[0072] (5) The organic phase was washed twice with an acetic acid / sodium acetate buffer solution with a pH of 5.5 and a sodium chloride concentration of 12 wt%. Each wash used 300 mL of buffer solution, and the mixture was stirred for 10 min and then allowed to stand for 20 min to separate into layers. Washing was stopped when the pH of the final wash phase was 5.2–5.8, and the difference between the conductivity of the final wash phase and the conductivity of the blank buffer solution in the same batch was no more than 10% of the conductivity of the blank buffer solution in the same batch. The moisture content of the organic phase after washing was controlled to be no higher than 0.3 wt%.

[0073] (6) The washed organic phase was concentrated under reduced pressure at -0.085 MPa and 28–32 °C, and then replaced with ethyl acetate with a peroxide content of no more than 50 ppm to obtain an ethyl acetate concentrate with a target intermediate concentration of 160 g / L. Isopropanol with a peroxide content of no more than 50 ppm was added to the concentrate to make the volume ratio of ethyl acetate to isopropanol 1:0.15, and the mixture was stirred at 32 °C until completely dissolved.

[0074] (7) Record the volume of ethyl acetate in the above solution to be crystallized as 1.0V. Add 0.50V of methyl tert-butyl ether with a peroxide content not exceeding 50ppm at 32℃ for 1.5h. After the system becomes slightly turbid, add seed crystals at 0.25wt% of the theoretical mass of the target intermediate and grow crystals at 32℃ for 90min. Then add 2.7V of n-heptane for 3h. After the addition is complete, cool to 3℃ at a rate of 0.15℃ / min and keep warm for 3h.

[0075] (8) The obtained crystal slurry was centrifuged and filtered. The filter cake was washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, with a volume ratio of ethyl acetate to n-heptane of 1:4. The amount of washing solution was 1.0 times the mass of the wet filter cake. After washing, the product was dried under reduced pressure at 32℃ and -0.085MPa to obtain the purified intermediate of cephalosporin, which was designated as sample S1.

[0076] Example 2:

[0077] This embodiment provides a method for purifying and preparing an intermediate of fluorocephalosporin, including the following steps:

[0078] (1) Take the crude intermediate of cephalosporin, calculate the content of the target cephalosporin intermediate according to the HPLC external standard method, add ethyl acetate with a peroxide content not exceeding 50 ppm, and prepare 1.0 L of organic phase with a target intermediate concentration of 90 g / L. Cool the organic phase to 5℃, add 200 mL of acetic acid / sodium acetate buffer solution with pH 5.3 and sodium chloride mass concentration of 10 wt%, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, stir for 8 min, let stand for 20 min, and separate the aqueous phase. Detect the moisture content of the organic phase and adjust the moisture content of the organic phase to 0.35 wt%; when the moisture content of the organic phase is lower than 0.35 wt%, add an appropriate amount of acetic acid / sodium acetate buffer solution with pH 5.3, stir and let stand to separate the layers; when the moisture content of the organic phase is higher than 0.35 wt%, dehydrate under reduced pressure for a short time at 20~30℃ and -0.095~-0.06 MPa.

[0079] (2) Add 200 mL of iodide pre-activation solution to the above organic phase. In the iodide pre-activation solution, the sodium chloride mass concentration is 14 wt%, the amount of potassium iodide is 0.003 equivalents of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.002 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 5.2. After addition, stir at 4℃ for 10 min, let stand for 20 min, and separate the aqueous phase.

[0080] (3) Add 300 mL of sulfite capture solution to the obtained organic phase. In the sulfite capture solution, the sodium chloride mass concentration is 10 wt%, the amount of sodium sulfite is 0.08 equivalents of the target intermediate molar amount, the amount of potassium iodide is 0.001 equivalents of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.002 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 5.8. After addition, stir at 6℃ for 70 min. During stirring, use an aqueous solution of acetic acid or sodium acetate to control the pH of the aqueous phase at 5.8-6.2. Let stand for 20 min, and then separate the aqueous phase.

[0081] (4) Add 200 mL of thiosulfate termination washing solution to the obtained organic phase. The thiosulfate termination washing solution contains 10 wt% sodium chloride, 0.010 equivalents of the target intermediate molar amount of sodium thiosulfate, a total concentration of acetic acid and sodium acetate of 0.10 mol / L, and a pH of 5.2 in the aqueous phase. After addition, stir at 4 °C for 20 min, let stand for 20 min, and then separate the aqueous phase.

[0082] (5) The organic phase was washed three times with an acetic acid / sodium acetate buffer solution with a pH of 5.3 and a sodium chloride concentration of 10 wt%. Each wash used 200 mL of buffer solution, and the phase was stirred for 8 min and then allowed to stand for 20 min to separate. Washing was stopped when the pH of the final wash phase was 5.2–5.8, and the difference between the conductivity of the final wash phase and the conductivity of the blank buffer solution in the same batch was no more than 10% of the conductivity of the blank buffer solution in the same batch. The moisture content of the organic phase after washing was controlled to be no higher than 0.5 wt%.

[0083] (6) The washed organic phase was concentrated under reduced pressure at -0.080 MPa and 25-30 °C, and then replaced with ethyl acetate with a peroxide content of no more than 50 ppm to obtain an ethyl acetate concentrate with a target intermediate concentration of 130 g / L. Isopropanol with a peroxide content of no more than 50 ppm was added to the concentrate to make the volume ratio of ethyl acetate to isopropanol 1:0.10, and the mixture was stirred at 28 °C until completely dissolved.

[0084] (7) Record the volume of ethyl acetate in the above solution to be crystallized as 1.0V. Add 0.30V of methyl tert-butyl ether with a peroxide content not exceeding 50ppm at 28℃ for 0.5h. After the system becomes slightly turbid, add seed crystals at 0.10wt% of the theoretical mass of the target intermediate and grow crystals at 28℃ for 120min. Then add 3.5V of n-heptane for 5h. After the addition is complete, cool to 0℃ at a rate of 0.10℃ / min and keep warm for 4h.

[0085] (8) The obtained crystal slurry was centrifuged and filtered. The filter cake was washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, with a volume ratio of ethyl acetate to n-heptane of 1:3. The amount of washing solution was 0.5 times the mass of the wet filter cake. After washing, the product was dried under reduced pressure at 30℃ and -0.080MPa to obtain the purified intermediate of cephalosporin, which was designated as sample S2.

[0086] Example 3:

[0087] This embodiment provides a method for purifying and preparing an intermediate of fluorocephalosporin, including the following steps:

[0088] (1) Take the crude intermediate of cephalosporin, calculate the content of the target cephalosporin intermediate according to the HPLC external standard method, add ethyl acetate with a peroxide content not exceeding 50 ppm, and prepare 1.0 L of organic phase with a target intermediate concentration of 140 g / L. Cool the organic phase to 10℃, add 450 mL of acetic acid / sodium acetate buffer solution with pH 5.7 and sodium chloride mass concentration of 16 wt%, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, stir for 20 min, let stand for 30 min, and separate the aqueous phase. Detect the moisture content of the organic phase and adjust the moisture content of the organic phase to 1.0 wt%; when the moisture content of the organic phase is less than 1.0 wt%, add an appropriate amount of acetic acid / sodium acetate buffer solution with pH 5.7, stir and let stand to separate the layers; when the moisture content of the organic phase is greater than 1.0 wt%, dehydrate under reduced pressure for a short time at 20~30℃ and -0.095~-0.06 MPa.

[0089] (2) Add 450 mL of iodide pre-activation solution to the above organic phase. In the iodide pre-activation solution, the sodium chloride mass concentration is 18 wt%, the potassium iodide amount is 0.012 equivalents of the target intermediate molar amount, the disodium ethylenediaminetetraacetate amount is 0.006 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 5.6. After addition, stir at 9 °C for 25 min, let stand for 30 min, and separate the aqueous phase.

[0090] (3) Add 650 mL of sulfite capture solution to the obtained organic phase. In the sulfite capture solution, the sodium chloride mass concentration is 15 wt%, the amount of sodium sulfite is 0.14 equivalents of the target intermediate molar amount, the amount of potassium iodide is 0.004 equivalents of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.004 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 6.1. After addition, stir at 10℃ for 40 min. During stirring, use an aqueous solution of acetic acid or sodium acetate to control the pH of the aqueous phase at 5.8-6.2. Let stand for 30 min, and then separate the aqueous phase.

[0091] (4) Add 450 mL of thiosulfate termination washing solution to the obtained organic phase. The thiosulfate termination washing solution contains 16 wt% sodium chloride, 0.025 equivalents of the target intermediate molar amount of sodium thiosulfate, a total concentration of acetic acid and sodium acetate of 0.10 mol / L, and a pH of 5.6 in the aqueous phase. After addition, stir at 10 °C for 8 min, let stand for 30 min, and then separate the aqueous phase.

[0092] (5) The organic phase was washed twice with an acetate / sodium acetate buffer solution with a pH of 5.6 and a sodium chloride concentration of 15 wt%. The volume of the buffer solution was 450 mL each time, and the mixture was stirred for 20 min and then allowed to stand for 30 min to separate into layers. The washing was stopped when the pH of the aqueous phase after the last wash was 5.2–5.8, and the difference between the conductivity of the aqueous phase after the last wash and the conductivity of the blank buffer solution in the same batch was not greater than 10% of the conductivity of the blank buffer solution in the same batch. The moisture content of the organic phase after washing was controlled to be no higher than 0.5 wt%.

[0093] (6) The washed organic phase was concentrated under reduced pressure at -0.095 MPa and 30–34 °C, and then replaced with ethyl acetate with a peroxide content of no more than 50 ppm to obtain an ethyl acetate concentrate with a target intermediate concentration of 185 g / L. Isopropanol with a peroxide content of no more than 50 ppm was added to the concentrate to make the volume ratio of ethyl acetate to isopropanol 1:0.22, and the mixture was stirred at 34 °C until completely dissolved.

[0094] (7) Record the volume of ethyl acetate in the above solution to be crystallized as 1.0V. Add 0.70V of methyl tert-butyl ether with a peroxide content not exceeding 50ppm at 34℃ for 2.5h. After the system becomes slightly turbid, add seed crystals at 0.40wt% of the theoretical mass of the target intermediate and grow crystals at 34℃ for 70min. Then add 2.2V of n-heptane for 1.5h. After the addition is complete, cool to 5℃ at a rate of 0.20℃ / min and keep warm for 2h.

[0095] (8) The obtained crystal slurry was centrifuged and filtered. The filter cake was washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, with a volume ratio of ethyl acetate to n-heptane of 1:5. The amount of washing solution was 1.5 times the mass of the wet filter cake. After washing, the product was dried under reduced pressure at 35℃ and -0.095MPa to obtain the purified intermediate of cephalosporin, which was designated as sample S3.

[0096] Example 4:

[0097] This embodiment provides a method for purifying and preparing an intermediate of fluorocephalosporin, including the following steps:

[0098] (1) Take the crude intermediate of cephalosporin, calculate the content of the target cephalosporin intermediate according to the HPLC external standard method, add ethyl acetate with a peroxide content not exceeding 50 ppm, and prepare 1.0 L of organic phase with a target intermediate concentration of 110 g / L. Cool the organic phase to 6℃, add 250 mL of acetic acid / sodium acetate buffer solution with pH 5.2 and sodium chloride mass concentration of 13 wt%, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, stir for 10 min, let stand for 20 min, and separate the aqueous phase. Detect the moisture content of the organic phase and adjust the moisture content of the organic phase to 0.5 wt%; when the moisture content of the organic phase is lower than 0.5 wt%, add an appropriate amount of acetic acid / sodium acetate buffer solution with pH 5.2, stir and let stand to separate the layers; when the moisture content of the organic phase is higher than 0.5 wt%, dehydrate under reduced pressure for a short time at 20~30℃ and -0.095~-0.06 MPa.

[0099] (2) Add 250 mL of iodide pre-activation solution to the above organic phase. In the iodide pre-activation solution, the sodium chloride mass concentration is 15 wt%, the potassium iodide amount is 0.005 equivalent of the target intermediate molar amount, the disodium ethylenediaminetetraacetate amount is 0.003 equivalent of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 5.2. After addition, stir at 5℃ for 10 min, let stand for 20 min, and separate the aqueous phase.

[0100] (3) Add 450 mL of sulfite capture solution to the obtained organic phase. In the sulfite capture solution, the sodium chloride mass concentration is 12 wt%, the amount of sodium sulfite is 0.09 equivalents of the target intermediate molar amount, the amount of potassium iodide is 0.002 equivalents of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.002 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 6.2. After addition, stir at 7℃ for 70 min. During stirring, use an aqueous solution of acetic acid or sodium acetate to control the pH of the aqueous phase at 5.8-6.2. Let stand for 20 min, and then separate the aqueous phase.

[0101] (4) Add 250 mL of thiosulfate termination washing solution to the obtained organic phase. The thiosulfate termination washing solution contains 12 wt% sodium chloride, 0.010 equivalents of the target intermediate molar amount of sodium thiosulfate, a total concentration of acetic acid and sodium acetate of 0.10 mol / L, and a pH of 5.3 in the aqueous phase. After addition, stir at 6 °C for 15 min, let stand for 20 min, and then separate the aqueous phase.

[0102] (5) The organic phase was washed three times with an acetic acid / sodium acetate buffer solution with a pH of 5.3 and a sodium chloride concentration of 12 wt%. Each wash used 250 mL of buffer solution, and the phase was stirred for 10 min and then allowed to stand for 20 min to separate into layers. Washing was stopped when the pH of the final wash phase was 5.2–5.8, and the difference between the conductivity of the final wash phase and the conductivity of the blank buffer solution in the same batch was no more than 10% of the conductivity of the blank buffer solution in the same batch. The moisture content of the organic phase after washing was controlled to be no higher than 0.3 wt%.

[0103] (6) The washed organic phase was concentrated under reduced pressure at -0.085 MPa and 25-30 °C, and then replaced with ethyl acetate with a peroxide content of no more than 50 ppm to obtain an ethyl acetate concentrate with a target intermediate concentration of 145 g / L. Isopropanol with a peroxide content of no more than 50 ppm was added to the concentrate to make the volume ratio of ethyl acetate to isopropanol 1:0.14, and the mixture was stirred at 30 °C until completely dissolved.

[0104] (7) Record the volume of ethyl acetate in the above crystallization solution as 1.0V. Add 0.45V of methyl tert-butyl ether with a peroxide content not exceeding 50ppm at 30℃ for 1.2h. After the system becomes slightly turbid, add seed crystals at 0.20wt% of the theoretical mass of the target intermediate and grow crystals at 30℃ for 100min. Then add 2.8V of n-heptane for 3.5h. After the addition is complete, cool to 2℃ at a rate of 0.15℃ / min and keep warm for 3h.

[0105] (8) The obtained crystal slurry was centrifuged and filtered. The filter cake was washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, with a volume ratio of ethyl acetate to n-heptane of 1:4. The amount of washing solution was 1.0 times the mass of the wet filter cake. After washing, the product was dried under reduced pressure at 32℃ and -0.085MPa to obtain the purified intermediate of fluorocephalosporin, which was designated as sample S4.

[0106] Example 5:

[0107] This embodiment provides a method for purifying and preparing an intermediate of fluorocephalosporin, including the following steps:

[0108] (1) Take the crude intermediate of cephalosporin, calculate the content of the target cephalosporin intermediate according to the HPLC external standard method, add ethyl acetate with a peroxide content not exceeding 50 ppm, and prepare 1.0 L of organic phase with a target intermediate concentration of 125 g / L. Cool the organic phase to 8℃, add 300 mL of acetic acid / sodium acetate buffer solution with pH 5.5 and sodium chloride mass concentration of 14 wt%, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, stir for 12 min, let stand for 20 min, and separate the aqueous phase. Detect the moisture content of the organic phase and adjust the moisture content of the organic phase to 0.8 wt%; when the moisture content of the organic phase is lower than 0.8 wt%, add an appropriate amount of acetic acid / sodium acetate buffer solution with pH 5.5, stir and let stand to separate the layers; when the moisture content of the organic phase is higher than 0.8 wt%, dehydrate under reduced pressure for a short time at 20~30℃ and -0.095~-0.06 MPa.

[0109] (2) Add 350 mL of iodide pre-activation solution to the above organic phase. In the iodide pre-activation solution, the sodium chloride mass concentration is 17 wt%, the amount of potassium iodide is 0.008 equivalents of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.004 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 5.4. After addition, stir at 6 °C for 18 min, let stand for 20 min, and separate the aqueous phase.

[0110] (3) Add 500 mL of sulfite capture solution to the obtained organic phase. In the sulfite capture solution, the sodium chloride mass concentration is 14 wt%, the amount of sodium sulfite is 0.10 equivalent of the target intermediate molar amount, the amount of potassium iodide is 0.003 equivalent of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.003 equivalent of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 6.0. After addition, stir at 9℃ for 50 min. During stirring, use an aqueous solution of acetic acid or sodium acetate to control the pH of the aqueous phase at 5.8-6.2. Let stand for 20 min, and then separate the aqueous phase.

[0111] (4) Add 300 mL of thiosulfate termination washing solution to the obtained organic phase. The thiosulfate termination washing solution contains 14 wt% sodium chloride, 0.015 equivalents of the target intermediate molar amount of sodium thiosulfate, a total concentration of acetic acid and sodium acetate of 0.10 mol / L, and a pH of 5.5 in the aqueous phase. After addition, stir at 8 °C for 12 min, let stand for 20 min, and then separate the aqueous phase.

[0112] (5) The organic phase was washed twice with an acetic acid / sodium acetate buffer solution with a pH of 5.5 and a sodium chloride concentration of 12 wt%. Each wash used 300 mL of buffer solution, and the mixture was stirred for 10 min and then allowed to stand for 20 min to separate into layers. Washing was stopped when the pH of the final wash phase was 5.2–5.8, and the difference between the conductivity of the final wash phase and the conductivity of the blank buffer solution in the same batch was no more than 10% of the conductivity of the blank buffer solution in the same batch. The moisture content of the organic phase after washing was controlled to be no higher than 0.3 wt%.

[0113] (6) The washed organic phase was concentrated under reduced pressure at -0.085 MPa and 28–32 °C, and then replaced with ethyl acetate with a peroxide content of no more than 50 ppm to obtain an ethyl acetate concentrate with a target intermediate concentration of 160 g / L. Isopropanol with a peroxide content of no more than 50 ppm was added to the concentrate to make the volume ratio of ethyl acetate to isopropanol 1:0.15, and the mixture was stirred at 32 °C until completely dissolved.

[0114] (7) Record the volume of ethyl acetate in the above solution to be crystallized as 1.0V. Add 0.30V of methyl tert-butyl ether with a peroxide content not exceeding 50ppm at 32℃ for 1h. After the system becomes slightly turbid, add seed crystals at 0.25wt% of the theoretical mass of the target intermediate and grow crystals at 32℃ for 100min. Then add 3.5V of n-heptane for 4h. After the addition is complete, cool to 3℃ at a rate of 0.12℃ / min and hold for 3h.

[0115] (8) The obtained crystal slurry was centrifuged and filtered. The filter cake was washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, with a volume ratio of ethyl acetate to n-heptane of 1:4. The amount of washing solution was 1.0 times the mass of the wet filter cake. After washing, the product was dried under reduced pressure at 32℃ and -0.085MPa to obtain the purified intermediate of cephalosporin, which was designated as sample S5.

[0116] Example 6:

[0117] This embodiment provides a method for purifying and preparing an intermediate of fluorocephalosporin, including the following steps:

[0118] (1) Take crude cephalosporin intermediate, calculate the target cephalosporin intermediate content using HPLC external standard method, add ethyl acetate with a peroxide content not exceeding 50 ppm, and prepare 50 L of organic phase with a target intermediate concentration of 130 g / L. Cool the organic phase to 8℃, add 15 L of acetic acid / sodium acetate buffer solution with pH 5.5 and sodium chloride mass concentration of 12 wt%, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, stir for 15 min, let stand for 30 min, and separate the aqueous phase. Detect the moisture content of the organic phase and adjust it to 0.7 wt%; when the organic phase moisture content is lower than 0.7 wt%, add an appropriate amount of acetic acid / sodium acetate buffer solution with pH 5.5, stir and let stand to separate the layers; when the organic phase moisture content is higher than 0.7 wt%, dehydrate under short-term reduced pressure at 20~30℃ and -0.095~-0.06 MPa.

[0119] (2) Add 17.5 L of iodide pre-activation solution to the above organic phase. In the iodide pre-activation solution, the sodium chloride mass concentration is 17 wt%, the amount of potassium iodide is 0.008 equivalents of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.004 equivalents of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 5.4. After addition, stir at 6℃ for 20 min, let stand for 30 min, and separate the aqueous phase; the stirring linear speed is controlled at 0.5~2.5 m / s.

[0120] (3) Add 25 L of sulfite capture solution to the obtained organic phase. In the sulfite capture solution, the sodium chloride mass concentration is 14 wt%, the amount of sodium sulfite is 0.10 equivalent of the target intermediate molar amount, the amount of potassium iodide is 0.003 equivalent of the target intermediate molar amount, the amount of disodium ethylenediaminetetraacetate is 0.003 equivalent of the target intermediate molar amount, the total concentration of acetic acid and sodium acetate is 0.10 mol / L, and the pH of the aqueous phase is 6.0. After addition, stir at 9℃ for 60 min. During stirring, use acetic acid or sodium acetate aqueous solution to control the pH of the aqueous phase at 5.8-6.2. Let stand for 30 min, and separate the aqueous phase. The stirring linear speed is controlled at 0.5-2.5 m / s.

[0121] (4) Add 15 L of thiosulfate termination washing solution to the obtained organic phase. The thiosulfate termination washing solution has a sodium chloride mass concentration of 14 wt%, a sodium thiosulfate amount of 0.015 equivalents of the target intermediate molar amount, a total acetic acid and sodium acetate concentration of 0.10 mol / L, and an aqueous phase pH of 5.5. After addition, stir at 8 °C for 15 min, let stand for 30 min, and then separate the aqueous phase.

[0122] (5) The organic phase was washed twice with an acetic acid / sodium acetate buffer solution with a pH of 5.5 and a sodium chloride concentration of 12 wt%. Each wash used 15 L of buffer solution, and the mixture was stirred for 15 min and then allowed to stand for 30 min to separate into layers. Washing was stopped when the pH of the final wash phase was 5.2–5.8, and the difference between the conductivity of the final wash phase and the conductivity of the blank buffer solution in the same batch was no more than 10% of the conductivity of the blank buffer solution in the same batch. The moisture content of the organic phase after washing was controlled to be no higher than 0.3 wt%.

[0123] (6) The washed organic phase was concentrated under reduced pressure at -0.085 MPa and 28–32 °C, and then replaced with ethyl acetate with a peroxide content of no more than 50 ppm to obtain an ethyl acetate concentrate with a target intermediate concentration of 165 g / L. Isopropanol with a peroxide content of no more than 50 ppm was added to the concentrate to make the volume ratio of ethyl acetate to isopropanol 1:0.15, and the mixture was stirred at 32 °C until completely dissolved.

[0124] (7) Record the volume of ethyl acetate in the above solution to be crystallized as 1.0V. Add 0.50V of methyl tert-butyl ether with a peroxide content not exceeding 50ppm at 32℃ for 2h. After the system becomes slightly turbid, add seed crystals at 0.25wt% of the theoretical mass of the target intermediate and grow crystals at 32℃ for 90min. Then add 2.7V of n-heptane for 4h. After the addition is complete, cool to 3℃ at a rate of 0.15℃ / min and keep warm for 3h.

[0125] (8) The obtained crystal slurry was centrifuged and filtered. The filter cake was washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, with a volume ratio of ethyl acetate to n-heptane of 1:4. The amount of washing solution was 1.0 times the mass of the wet filter cake. After washing, the product was dried under reduced pressure at 32℃ and -0.085MPa to obtain the purified intermediate of cephalosporin, which was designated as sample S6.

[0126] Comparative Example 1:

[0127] Compared to Example 1, the difference is that the organic phase moisture adjustment step is omitted. After initial washing with buffered brine and separation of the aqueous phase, the iodide pre-activation treatment is performed directly. All other aspects are the same. The resulting sample is designated as D1.

[0128] Comparative Example 2:

[0129] Compared to Example 1, the difference lies in the following: the separate operations of iodide pre-activation treatment and sulfite capture treatment are omitted; the iodide pre-activation solution and sulfite capture solution from Example 1 are combined into a single aqueous treatment solution and added at once; the total amounts of potassium iodide, sodium sulfite, disodium EDTA, and sodium chloride in the combined aqueous treatment solution are the same as in Example 1, the pH of the aqueous phase is controlled at 6.0, the treatment temperature is 9°C, the stirring time is 68 min, and all other parameters are the same. The resulting sample is designated as D2.

[0130] Comparative Example 3:

[0131] Compared to Example 1, the difference lies in that potassium iodide was not added to either the iodide pre-activation solution or the sulfite capture solution, and the aqueous phase volume was made up with the same volume of acetate / sodium acetate buffer solution; all other aspects remained the same. The resulting sample was designated D3.

[0132] Comparative Example 4:

[0133] Compared to Example 1, the difference is that sodium sulfite was not added to the sulfite capture solution, and the aqueous phase volume was made up with the same volume of acetate / sodium acetate buffer solution; all other aspects were the same. The resulting sample was designated D4.

[0134] Comparative Example 5:

[0135] Compared to Example 1, the difference lies in that disodium ethylenediaminetetraacetate was not added to either the iodide pre-activation solution or the sulfite capture solution; all other aspects remained the same. The resulting sample was designated D5.

[0136] Comparative Example 6:

[0137] Compared to Example 1, the difference lies in that: the thiosulfate termination washing step is omitted; after sulfite capture treatment and separation of the aqueous phase, subsequent acetic acid / sodium acetate buffered brine washing is performed directly; all other aspects are the same. The resulting sample is designated D6.

[0138] Comparative Example 7:

[0139] Compared to Example 1, the difference lies in that the subsequent acetate / sodium acetate buffered saline wash did not use pH and conductivity as washing endpoints, but was only washed once with a fixed washing solution volume of 300 mL; all other aspects remained the same. The resulting sample was designated D7.

[0140] Comparative Example 8:

[0141] Compared with Example 1, the differences are as follows: methyl tert-butyl ether was not used to induce nucleation in the crystallization step; after the ethyl acetate / isopropanol system was completely dissolved, n-heptane 3.2V was added dropwise over a period of 4.5 hours, followed by the same cooling, holding, filtering, washing, and drying conditions as in Example 1. The resulting sample was designated D8.

[0142] Comparative Example 9:

[0143] Compared to Example 1, the difference lies in the reverse order of adding the antisolvent during the crystallization step: first, n-heptane at 2.7V is added dropwise; after the addition is complete, seed crystals are added and crystallized for 90 minutes; then, methyl tert-butyl ether at 0.50V is added dropwise. The rest is the same. The resulting sample is designated D9.

[0144] Comparative Example 10:

[0145] Compared to Example 1, the differences are as follows: Iodide pre-activation treatment, sulfite capture treatment, and thiosulfate termination washing are omitted; after initial buffer brine washing and adjustment of the organic phase moisture content, the sample is directly washed twice with an acetate / sodium acetate buffer brine at pH 5.5 and a sodium chloride mass concentration of 12 wt%, followed by subsequent concentration, solvent replacement, crystallization, and drying; all other steps are the same. The resulting sample is designated D10.

[0146] Test Example 1:

[0147] The testing steps are as follows:

[0148] (1) The organic phase before iodide preactivation, the organic phase after iodide preactivation, the organic phase after sulfite capture, and the aqueous phase after sulfite capture in Example 1 were taken as the test objects; the organic phase and aqueous phase of the corresponding stage in Comparative Example 3, Comparative Example 4 and Comparative Example 10 were taken as the control test objects.

[0149] (2) Organic phase samples were diluted with acetonitrile, filtered, and then analyzed by HPLC to record the content of halomethyl impurities. Aqueous phase samples were diluted with an acetonitrile / water mixed solvent, filtered, and then analyzed by LC-MS or LC-MS / MS with an acetonitrile to water volume ratio of 1:1. The extraction ion current response values ​​of sulfonate conversion products and halomethyl impurities were recorded. Blank buffer saline of the same batch was simultaneously detected during the analysis to subtract the background response.

[0150] (3) HPLC detection was performed using a C18 column. Mobile phase A was 0.02 mol / L ammonium acetate aqueous solution, and mobile phase B was acetonitrile. Gradient elution was used. The detection wavelength was 254 nm, the column temperature was 30 ℃, the flow rate was 1.0 mL / min, and the injection volume was 10 μL. LC-MS or LC-MS / MS detection was performed using an electrospray ionization source, scanning in both positive and negative ion modes. Each sample was detected in triplicate, and the average value was taken as the detection result.

[0151] The test results are shown in Table 1.

[0152]

[0153] Note: "Not Applicable" indicates that this test item is not applicable to the corresponding sample type. The response values ​​of sulfonate conversion products and halomethyl impurities are LC-MS extracted ion current response values ​​after background subtraction of the same batch of blank buffer saline, and are used for relative comparison between aqueous samples of the same batch.

[0154] According to the data in Table 1, in Example 1, the content of halomethyl impurities in the organic phase before iodide preactivation was 0.384%, and after iodide preactivation it was 0.347%, which decreased to 0.047% after sulfite capture; the corresponding response value of sulfonate conversion products in the captured aqueous phase was 8.91 × 10⁻⁶. 5 Combining Figures 1-3 It can be seen that after capture in Example 1, the peak response of halomethyl impurities in the organic phase decreased, while the peak response of sulfonate conversion products in the aqueous phase increased. This result indicates a correlation between the sulfite capture step and the transfer of halomethyl impurities from the organic phase to the aqueous phase.

[0155] According to the data in Table 1, in Comparative Examples 3, 4, and 10, the contents of halomethyl impurities in the organic phase were 0.286%, 0.319%, and 0.358%, respectively, and the corresponding response values ​​of sulfonate conversion products in the aqueous phase were 1.24 × 10⁻⁶. 5 0.19×10 5 and 0.11×10 5 Compared to Example 1, the comparative example above showed higher residual levels of halomethyl impurities in the organic phase and lower response of sulfonate conversion products in the aqueous phase. This result indicates that the degree to which halomethyl impurities are converted into water-soluble sulfonates and enter the aqueous phase is lower when iodide pre-activation, sulfite capture, or only ordinary buffered brine washing is used. These results can serve as the experimental basis for the stepwise reaction extraction using iodide pre-activation and sulfite capture in this invention.

[0156] Test Example 2:

[0157] The testing steps are as follows:

[0158] (1) Sample S1 obtained in Example 1 and sample D2 obtained in Comparative Example 2 were taken as the product testing objects; the organic phase after sulfite capture in Example 1, the aqueous phase after sulfite capture in Example 1, the organic phase after mixed treatment in Comparative Example 2, and the aqueous phase after mixed treatment in Comparative Example 2 were taken as the process testing objects.

[0159] (2) After dilution and filtration with acetonitrile, the product sample and organic phase sample were subjected to HPLC detection. The main peak of the target intermediate, the halomethyl impurity peak, and other related substances peaks were recorded. The content of the main peak of the target intermediate was calculated by the external standard method, and the content of halomethyl impurities and total related substances was calculated by the area normalization method. HPLC detection was performed using a C18 column, with mobile phase A being 0.02 mol / L ammonium acetate aqueous solution and mobile phase B being acetonitrile. Gradient elution was used, the detection wavelength was 254 nm, the column temperature was 30 ℃, the flow rate was 1.0 mL / min, and the injection volume was 10 μL.

[0160] (3) Aqueous phase samples were diluted with acetonitrile / water mixed solvent, filtered, and then analyzed by LC-MS. The volume ratio of acetonitrile to water was 1:1. The response values ​​of sulfonate conversion products were recorded by extractive ion chromatography. Product samples were extracted with the specified volume of water according to the sample mass. Organic phase samples were extracted with an equal volume of water and then analyzed for iodide ion and sulfite residues by ion chromatography. Each sample was analyzed in triplicate, and the average value was taken as the detection result.

[0161] The test results are shown in Table 2.

[0162]

[0163] Note: "Not Applicable" indicates that this test item is not applicable to the corresponding sample type. Iodide ions and sulfite ions in product samples and organic phase samples are the results of ion chromatography detection after extraction with an equal volume of water; iodide ions and sulfite ions in aqueous phase samples are the results of direct detection in the aqueous phase. The response value of aqueous phase sulfonate conversion products is the LC-MS extracted ion current response value after background subtraction of the same batch of blank buffer saline, used for relative comparison between aqueous phase samples of the same batch.

[0164] According to the data in Table 2, after staged reaction extraction in Example 1, the target intermediate peak content in sample S1 was 99.24%, the halomethyl impurity content was 0.046%, and the total related substances were 0.36%. After a single mixing process in Comparative Example 2, the target intermediate peak content in sample D2 was 98.67%, the halomethyl impurity content was 0.154%, and the total related substances were 0.91%. Simultaneously, during the preparation of sample S1, the response value of the sulfonate conversion products captured in the aqueous phase in Example 1 was 8.91 × 10⁻⁶. 5 During the preparation of sample D2, the corresponding response value in the aqueous phase of Comparative Example 2 was 3.28 × 10⁻⁶. 5 Combining Figure 4 It can be seen that the organic phase halomethyl impurity peaks are lower in the segmented treatment system, while the aqueous phase sulfonate conversion products have higher responses.

[0165] According to the data in Table 2, the iodide and sulfite concentrations in the organic phase after the mixed treatment in Comparative Example 2 were 21.3 mg / L and 31.8 mg / L, respectively, which were higher than the 6.2 mg / L and 4.4 mg / L in the organic phase after capture in Example 1. The residual sulfite concentration in the aqueous phase after the mixed treatment in Comparative Example 2 was 64.1 mg / L, also higher than the 12.5 mg / L in the aqueous phase captured in Example 1. These results indicate that the degree of conversion of halomethyl impurities and the state of inorganic ion removal differ between single-stage mixed treatment and staged treatment. Therefore, staged iodide pre-activation and sulfite capture are beneficial for establishing a temporal coordination between pre-activation and capture, facilitating the transfer of halomethyl impurities to sulfonate conversion products in the aqueous phase, and reducing the entrainment of inorganic ions in the subsequent organic phase.

[0166] Test Example 3:

[0167] The testing steps are as follows:

[0168] (1) Take the sample S1 obtained in Example 1, the sample D1 obtained in Comparative Example 1, the sample D6 obtained in Comparative Example 6 and the sample D7 obtained in Comparative Example 7 as the product testing objects; take the organic phase before iodide preactivation, the organic phase after sulfite capture, the organic phase after termination washing or the corresponding organic phase after washing, and the aqueous phase of the last washing in Example 1, Comparative Example 1, Comparative Example 6 and Comparative Example 7 as the process testing objects.

[0169] (2) The water content of the organic phase before iodide preactivation was determined by Karl Fischer method; the time for the phase separation after sulfite capture and standing until the interface between the two phases was clear was recorded; the pH of the last wash phase was determined by pH meter; the conductivity of the last wash phase and the blank buffer brine of the same batch were determined by conductivity meter, and the ratio of the difference between the two was calculated.

[0170] (3) Take the organic phase after the final washing or the corresponding organic phase after washing, extract it with an equal volume of water, and then use ion chromatography to detect the residues of iodide ions, sulfite ions, and thiosulfate ions. Take the product sample, dissolve it in acetonitrile, dilute it, filter it, and then perform HPLC analysis. Record the halomethyl impurities, thioether oxide impurities, and total related substances. Each sample is analyzed in parallel 3 times, and the average value is taken as the detection result.

[0171] The test results are shown in Table 3.

[0172]

[0173] Note: "Not detected" indicates that the detection result is below the detection limit of this method. The percentage difference in conductivity of the washing aqueous phase is calculated as "the difference between the conductivity of the last washing aqueous phase and the conductivity of the blank buffer saline in the same batch / the conductivity of the blank buffer saline in the same batch × 100%". Iodide ions, sulfite ions, and thiosulfate ions in the aqueous extract are the results of ion chromatography detection after equal volume water extraction of the organic phase.

[0174] According to the data in Table 3, in Example 1, the organic phase moisture content before iodide pre-activation was 0.70 wt%, the phase separation time after sulfite capture was 18.6 min, the pH of the final washing aqueous phase was 5.48, and the conductivity difference ratio of the washing aqueous phase was 5.7%. The content of halomethyl impurities in sample S1 was 0.046%, the content of sulfide oxide impurities was 0.052%, and the total related substances were 0.36%. In Comparative Example 1, no organic phase moisture pre-adjustment was performed, the organic phase moisture content was 0.18 wt%, the phase separation time after sulfite capture was 34.2 min, the content of halomethyl impurities in sample D1 was 0.126%, and the total related substances were 0.78%. These results show a certain correlation between the organic phase moisture state and the phase separation time and the residual halomethyl impurities.

[0175] According to the data in Table 3, Comparative Example 6 did not undergo thiosulfate-terminated washing, and the iodide ion concentration in the aqueous extract was 24.9 mg / L. The content of thioether oxide impurities in Sample D6 was 0.143%, both higher than that in Sample S1. Comparative Example 7 underwent a fixed single wash without pH / conductivity endpoint control. The pH of the aqueous phase in the final wash was 6.13, the conductivity difference ratio was 31.8%, and the iodide, sulfite, and thiosulfate ion concentrations in the aqueous extract were 18.6 mg / L, 22.4 mg / L, and 29.7 mg / L, respectively, with a total related substances of 0.66%. These results indicate that thiosulfate-terminated washing is related to a decrease in residual iodine-related components, and pH / conductivity endpoint control can reflect the degree of washing completion. In summary, organic phase moisture pre-conditioning, thiosulfate-terminated washing, and pH / conductivity washing endpoint control correspond to the interface state before reaction extraction, the residual active components after capture, and the washing state control, respectively. The combination of these three methods helps improve the controllability of the purification process.

[0176] Test Example 4:

[0177] The testing steps are as follows:

[0178] (1) Sample S1 obtained in Example 1 and sample D5 obtained in Comparative Example 5 were used as the product testing objects; the organic phase before concentration and the solution to be crystallized after concentration in Example 1 and Comparative Example 5 were used as the process testing objects. The difference between Comparative Example 5 and Example 1 is that disodium ethylenediaminetetraacetate was not added to either the iodide pre-activation solution or the sulfite capture solution.

[0179] (2) Take samples from each process and product, dilute or dissolve them in acetonitrile, filter them, and then perform HPLC analysis. Record the sulfide oxidation impurities and total related substances. HPLC analysis uses a C18 column, with mobile phase A being 0.02 mol / L ammonium acetate aqueous solution and mobile phase B being acetonitrile. Gradient elution is used, the detection wavelength is 254 nm, the column temperature is 30 ℃, the flow rate is 1.0 mL / min, and the injection volume is 10 μL. The sulfide oxidation impurity peaks can be assigned using LC-MS or LC-MS / MS. The content of sulfide oxidation impurities and total related substances is calculated using the HPLC area normalization method.

[0180] (3) Take samples from each process and product, and after digestion, use ICP-OES or ICP-MS to detect iron, copper and titanium residues; take ethyl acetate, isopropanol and methyl tert-butyl ether used in Example 1 and Comparative Example 5 to detect peroxide content. Each sample is tested in parallel 3 times, and the average value is taken as the test result.

[0181] The test results are shown in Tables 4-1 and 4-2.

[0182]

[0183]

[0184] Note: In Table 4-1, the residual amounts of iron, copper, and titanium are the elemental contents calculated based on the sample mass after digestion. The peroxide content in Table 4-2 is the result of the detection of solvents used in the same batch, and does not represent the peroxide content of the process sample or product sample itself.

[0185] According to the data in Table 4-1, in Example 1, the content of sulfide oxide impurities changed from 0.031% in the organic phase before concentration to 0.043% in the concentrated crystallization solution, and was 0.052% in sample S1. In Comparative Example 5, without the addition of disodium ethylenediaminetetraacetate, the content of sulfide oxide impurities changed from 0.064% in the organic phase before concentration to 0.116% in the concentrated crystallization solution, and was 0.151% in sample D5. Meanwhile, the residual levels of iron, copper, and titanium in Comparative Example 5 were higher than in Example 1. These results show a correlation between the addition of disodium ethylenediaminetetraacetate and the reduction in trace metal residues and the slowing of the growth of sulfide oxide impurities.

[0186] According to the data in Table 4-2, the peroxide content in ethyl acetate, isopropanol, and methyl tert-butyl ether used in Example 1 and Comparative Example 5 was all below 50 ppm, indicating that both experiments were conducted under low-peroxide solvent conditions. Under these conditions, the levels of sulfide oxidation impurities and total related substances in Comparative Example 5 were still higher than in Example 1, indicating that low-peroxide solvent control can reduce the influence of exogenous peroxides, while the metal complexation control of disodium ethylenediaminetetraacetate is related to reducing the increase of sulfide oxidation impurities. These results can serve as the experimental basis for the use of metal complexation control and low-peroxide solvent control in this invention.

[0187] Test Example 5:

[0188] The testing steps are as follows:

[0189] (1) Sample S1 obtained in Example 1, sample D8 obtained in Comparative Example 8, and sample D9 obtained in Comparative Example 9 were taken as the product testing objects; the mother liquor and filter cake washing liquid after crystallization and filtration in Example 1, Comparative Example 8, and Comparative Example 9 were taken as the process testing objects. In Example 1, methyl tert-butyl ether was used to induce nucleation first, followed by growth and crystallization in n-heptane; in Comparative Example 8, n-heptane was used directly for crystallization; in Comparative Example 9, n-heptane was added first, followed by methyl tert-butyl ether.

[0190] (2) The product samples, crystallization mother liquor, and filter cake washing liquid were diluted or dissolved in acetonitrile and filtered before HPLC analysis. The content of the main peak of the target intermediate in the product sample was calculated by the external standard method, and the content of halomethyl impurities and total related substances was calculated by the area normalization method; the content of the target intermediate in the mother liquor and washing liquid was calculated by the external standard method.

[0191] (3) Turbidity changes in the system were recorded using a turbidimeter during the addition of the antisolvent. The turbidity at the start of antisolvent addition was taken as the baseline. The point at which the turbidity increased by at least 10 NTU from the baseline and remained so for more than 5 minutes was recorded as the turbidity initiation point. The amount of antisolvent added at the time of turbidity initiation and the relative fluctuation of turbidity within 20 minutes after turbidity initiation were recorded. After drying, the product was tested for ethyl acetate, isopropanol, methyl tert-butyl ether, and n-heptane residues using gas chromatography. Each sample was tested in triplicate, and the average value was taken as the test result.

[0192] The test results are shown in Tables 5-1 and 5-2.

[0193]

[0194] Note: The amount of antisolvent added when turbidity occurs is calculated based on the volume of ethyl acetate in the solution to be crystallized being 1.0V. For D8 and D9, the amount of antisolvent added when turbidity occurs is the amount of n-heptane added. The relative fluctuation of turbidity 20 minutes after turbidity occurs is calculated as the ratio of the standard deviation of turbidity to the average turbidity during that period.

[0195]

[0196] Note: "Not detected" indicates that the detection result is below the detection limit of this method. The total residual solvent is the sum of the residual solvents listed in the table.

[0197] According to the data in Table 5-1, in Example 1, the system reached its turbidity point when the amount of methyl tert-butyl ether added was 0.43V, and the relative turbidity fluctuation after 20 minutes was 6.8%. In Comparative Example 8, n-heptane was directly added for crystallization, and the amount of n-heptane added at the time of turbidity was 0.61V, with a relative turbidity fluctuation of 28.5%. In Comparative Example 9, n-heptane was added first, and the amount of n-heptane added at the time of turbidity was 0.76V, with a relative turbidity fluctuation of 19.7%. These results show that when methyl tert-butyl ether is added first, the turbidity process is easier to control, and the turbidity fluctuation after turbidity is lower. When n-heptane is added directly for crystallization or when the antisolvent is added in reverse, the turbidity fluctuation is larger.

[0198] According to the data in Tables 5-1 and 5-2, the main peak content of the product in sample S1 was 99.24%, the content of halomethyl impurities was 0.046%, the total related substances were 0.36%, and the total residual solvent was 5030 ppm. In samples D8 and D9, the halomethyl impurity contents were 0.131% and 0.119%, respectively, the total related substances were 1.08% and 0.94%, respectively, and the total residual solvent was 6370 ppm and 7340 ppm, respectively. The low content of the target intermediate in the mother liquor of D8 but the high content of related substances suggest that direct n-heptane crystallization may increase impurity entrainment or co-precipitation. The high content of the target intermediate in the mother liquor of D9 suggests that the precipitation process of the target intermediate was insufficient when the antisolvent was added in the reverse direction. These results indicate that the sequential control of methyl tert-butyl ether nucleation followed by n-heptane crystallization, compared with direct n-heptane crystallization or the addition of the antisolvent in the reverse direction, shows better overall performance in terms of crystallization process stability, control of related substances, and solvent entrainment in the filter cake.

[0199] Test Example 6:

[0200] The testing steps are as follows:

[0201] (1) Samples S1 to S6 obtained from Examples 1 to 6 and samples D1 to D10 obtained from Comparative Examples 1 to 10 were taken as the test objects.

[0202] (2) Each sample was dissolved, diluted, and filtered in acetonitrile before HPLC detection. The main peak of the target intermediate, the peak of halomethyl impurities, the peak of thioether oxide impurities, and other related substances were recorded. The content of the main peak of the target intermediate was calculated using the external standard method, while the contents of halomethyl impurities, thioether oxide impurities, other maximum single impurities, and total related substances were calculated using the area normalization method. HPLC detection was performed using a C18 column. Mobile phase A was 0.02 mol / L ammonium acetate aqueous solution, and mobile phase B was acetonitrile. Gradient elution was used. The detection wavelength was 254 nm, the column temperature was 30 ℃, the flow rate was 1.0 mL / min, and the injection volume was 10 μL.

[0203] (3) The Karl Fischer method was used to determine the moisture content of the samples; the residual solvent detection method was used to detect the residues of ethyl acetate, isopropanol, methyl tert-butyl ether, and n-heptane; after extraction with a specified volume of water according to the sample mass, iodide ions, sulfite ions, and thiosulfate ions were detected by ion chromatography; after digestion, the residues of iron, copper, and titanium were detected by ICP-OES or ICP-MS. Each sample was tested in parallel three times, and the average value was taken as the test result.

[0204] The test results are shown in Tables 6-1 and 6-2.

[0205]

[0206] Note: The total residual solvent is the sum of the residual amounts of ethyl acetate, isopropanol, methyl tert-butyl ether, and n-heptane. Other maximum single impurity contents do not include halomethyl impurities and thioether oxide impurities listed separately in the table.

[0207]

[0208] Note: "Not detected" indicates that the detection result is below the detection limit of this method. Iodide ions, sulfite ions, and thiosulfate ions in the water extract are the results of ion chromatography detection after water extraction of the sample.

[0209] According to the data in Table 6-1, the main peak content of the target intermediate in samples S1-S6 obtained in Examples 1-6, calculated by external standard method, was 99.02%-99.24%, the content of halomethyl impurities was 0.046%-0.064%, the content of sulfide oxide impurities was 0.052%-0.069%, and the total related substances were 0.36%-0.50%. This result shows that the quality difference of the samples obtained by the process of this invention is small under different parameter combinations, indicating that the process parameter range has certain applicability.

[0210] Based on the data in Tables 6-1 and 6-2, different changes occurred in the corresponding indicators in the comparative examples where the reaction extraction-related steps were omitted or modified. In D1, no organic phase moisture pre-adjustment was performed, and the halomethyl impurity content was 0.126%. In D2, a single-stage mixing treatment was used, and the halomethyl impurity content was 0.154%, with iodide and sulfite concentrations in the aqueous extract being 18.4 mg / L and 27.6 mg / L, respectively. In D3 and D4, no potassium iodide was added, and the halomethyl impurity contents were 0.286% and 0.319%, respectively, without the addition of sodium sulfite. These results indicate that the organic phase moisture state, iodide pre-activation, and sulfite capture are all related to the control of halomethyl impurities and the phase transfer process.

[0211] Based on the data in Tables 6-1 and 6-2, D5, without the addition of disodium ethylenediaminetetraacetate, had a thioether oxide impurity content of 0.151%, with residual iron, copper, and titanium at 0.47 mg / kg, 0.16 mg / kg, and 0.23 mg / kg, respectively. D6, without thiosulfate-terminated washing, had a thioether oxide impurity content of 0.143%, and iodide ion concentration in the aqueous extract of 24.9 mg / L. D7, without pH / conductivity endpoint control, had iodide ion, sulfite, and thiosulfate ion concentrations of 18.6 mg / L, 22.4 mg / L, and 29.7 mg / L, respectively. These results indicate that metal complexation control, thiosulfate-terminated washing, and pH / conductivity endpoint control are related to the control of oxide impurities, the reduction of residual iodine-related components, and the degree of washing completion, respectively.

[0212] According to the data in Table 6-1, D8 was crystallized directly using n-heptane, with a halomethyl impurity content of 0.131% and a total related matter content of 1.08%; D9 was crystallized by adding n-heptane first and then methyl tert-butyl ether, with a halomethyl impurity content of 0.119%, a total related matter content of 0.94%, and a residual solvent content of 7340 ppm; D10 was crystallized directly after washing with ordinary buffer brine, with a halomethyl impurity content of 0.358% and a total related matter content of 1.74%. These results show that sequential antisolvent crystallization affects crystallization selectivity and residual solvent control, and ordinary buffer brine washing is difficult to replace the fractional reaction extraction and sequential crystallization process.

[0213] The data from Tables 6-1 and 6-2 show that Examples 1 to 6 are generally superior to the comparative examples in terms of the main peak content of the target intermediate, control of halomethyl impurities, control of thioether oxidation impurities, control of total related substances, and control of residual metal ions. The comparative examples, due to the omission or alteration of corresponding steps, exhibited unfavorable changes in at least one aspect, such as halomethyl impurities, thioether oxidation impurities, total related substances, residual inorganic ions, or residual solvents. These results indicate that the process of the present invention, consisting of organic phase moisture pre-conditioning, iodide pre-activation, sulfite capture, metal complexation, thiosulfate termination washing, pH / conductivity endpoint washing, and sequential antisolvent crystallization of methyl tert-butyl ether / n-heptane, corresponds to process control of interface state, impurity phase inversion, oxidation control, residual active component removal, washing state, and crystallization selectivity, and has a comprehensive impact on the purification process of cephalosporin intermediates.

[0214] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for purifying and preparing an intermediate of fluorocephalosporin, characterized in that, Includes the following steps: (1) Dissolve or disperse the crude intermediate of fluorocephalosporin to be purified in ethyl acetate to obtain an organic phase containing the target fluorocephalosporin intermediate, and adjust the moisture content of the organic phase; (2) The organic phase obtained in step (1) is contacted with an iodide pre-activation solution containing iodide and disodium ethylenediaminetetraacetate to perform iodide pre-activation treatment. After standing and separating the layers, the aqueous phase is removed. (3) Contact the organic phase obtained in step (2) with a sulfite capturing solution containing sulfite, iodide and disodium ethylenediaminetetraacetate to carry out sulfite capturing treatment, and separate the aqueous phase after standing and separating the layers. (4) Contact the organic phase obtained in step (3) with the terminating washing solution containing thiosulfate to perform terminating washing, and separate the aqueous phase after standing and separating the layers. (5) The organic phase obtained in step (4) is washed with buffer brine, then concentrated under reduced pressure and replaced with ethyl acetate solvent to obtain ethyl acetate concentrate, and isopropanol is added to the ethyl acetate concentrate to obtain the solution to be crystallized; (6) Methyl tert-butyl ether is added to the crystallization solution obtained in step (5) to induce nucleation, seed crystals are added to grow crystals, and then n-heptane is added to crystallize. After solid-liquid separation, washing and drying, the purified intermediate of fluorocephalosporin is obtained.

2. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (1), the concentration of the target cephalosporin intermediate in the organic phase is 90-140 g / L; before adjusting the moisture content, the organic phase is washed with an acetic acid / sodium acetate buffer solution with a pH of 5.2-5.7 and a sodium chloride mass concentration of 10-16 wt%; the moisture content of the organic phase is adjusted to 0.35-1.0 wt%.

3. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (2), the iodide is potassium iodide; the iodide pre-activation solution also contains sodium chloride and an acetic acid / sodium acetate buffer system; in the iodide pre-activation solution, the sodium chloride mass concentration is 14-18 wt%, the amount of potassium iodide is 0.003-0.012 equivalents of the target cephalosporin intermediate, the amount of disodium ethylenediaminetetraacetate is 0.002-0.006 equivalents of the target cephalosporin intermediate, and the pH of the aqueous phase is 5.2-5.6; the temperature of the iodide pre-activation treatment is 4-10℃, and the time is 10-25 min.

4. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (3), the sulfite is sodium sulfite, and the iodide is potassium iodide; the sulfite capturing solution also contains sodium chloride and an acetic acid / sodium acetate buffer system; in the sulfite capturing solution, the sodium chloride mass concentration is 10-15 wt%, the amount of sodium sulfite is 0.08-0.14 equivalents of the target cephalosporin intermediate, the amount of potassium iodide is 0.001-0.004 equivalents of the target cephalosporin intermediate, the amount of disodium ethylenediaminetetraacetate is 0.002-0.004 equivalents of the target cephalosporin intermediate, and the pH of the aqueous phase is 5.8-6.2; the temperature of the sulfite capturing treatment is 6-10℃, and the time is 40-70 min.

5. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (4), the thiosulfate is sodium thiosulfate; the terminating wash solution also contains sodium chloride and an acetic acid / sodium acetate buffer system; in the terminating wash solution, the sodium chloride mass concentration is 10-16 wt%, the amount of sodium thiosulfate is 0.010-0.025 equivalents of the target cephalosporin intermediate, and the pH of the aqueous phase is 5.2-5.6; the terminating wash temperature is 4-10℃, and the time is 8-20 min.

6. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (5), the buffer brine is an acetic acid / sodium acetate buffer brine with a pH of 5.2 to 5.8 and a sodium chloride concentration of 10 to 15 wt%; the washing is performed 2 to 3 times; the pH of the aqueous phase after the last wash is 5.2 to 5.8, and the difference between the conductivity of the aqueous phase after the last wash and the conductivity of the blank buffer brine in the same batch is not greater than 10% of the conductivity of the blank buffer brine in the same batch; the moisture content of the organic phase after washing is not higher than 0.5 wt%.

7. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (5), the vacuum concentration is carried out at -0.095 to -0.080 MPa and 25 to 34°C; the concentration of the target cephalosporin intermediate in the ethyl acetate concentrate is 130 to 185 g / L; after adding isopropanol to the ethyl acetate concentrate, the volume ratio of ethyl acetate to isopropanol is 1:(0.10 to 0.22).

8. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (6), with the volume of ethyl acetate in the solution to be crystallized being 1.0V, the amount of methyl tert-butyl ether added is 0.30-0.70V, and the dropping time is 0.5-2.5h; after the system becomes turbid, seed crystals are added, with the amount of seed crystals added being 0.10-0.40wt% of the theoretical mass of the target cephalosporin intermediate, and the crystal growth time is 70-120min; the amount of n-heptane added is 2.2-3.5V, and the dropping time is 1.5-5h.

9. The method for purifying and preparing the intermediate of fluorocephalosporin according to claim 1, characterized in that, In step (6), after adding n-heptane, the temperature is lowered to 0-5℃ at a rate of 0.10-0.20℃ / min and kept at this temperature for 2-4 hours. The filter cake obtained from solid-liquid separation is washed with a mixed solvent of ethyl acetate / n-heptane at 0-5℃, wherein the volume ratio of ethyl acetate to n-heptane is 1:(3-5), and the amount of washing liquid used is 0.5-1.5 times the mass of the wet filter cake.

10. The method for purifying and preparing the intermediate of fluorocephalosporin according to any one of claims 1-9, characterized in that, The peroxide content of ethyl acetate, isopropanol, and methyl tert-butyl ether is not higher than 50 ppm; in the obtained purified fluorocephalosporin intermediate, the main peak content of the target fluorocephalosporin intermediate is not lower than 99.0%, the content of halomethyl impurities is not higher than 0.065%, the content of thioether oxide impurities is not higher than 0.070%, and the total related substances are not higher than 0.50%.

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