A method of preparing polaprezinc

Abstract

The present application relates to the technical field of pharmacy, and particularly relates to a preparation method of polaprezinc, which comprises the following steps: taking L-serine as a starting material, reacting with acetyl chloride to obtain N-acetyl-L-serine, reacting with 4-bromo-1H-imidazole under the action of a catalyst to obtain N-acetyl-L-histidine, then reacting with an aldehyde and an amine salt under the action of a zinc salt, and finally preparing the target product polaprezinc by controlling the pH of a reaction solution. The preparation method can realize effective control of impurities in each step by chemically synthesizing polaprezinc, the maximum single impurity content in the obtained polaprezinc is less than or equal to 0.03%, and the total impurity content is less than or equal to 0.1%, thereby meeting the high-purity requirement of crude drugs in the technical field of pharmacy. The polaprezinc preparation method has the characteristics of high purity, high yield, low raw material cost, low energy consumption, low equipment requirement and the like, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing polyprezinc, belonging to the field of pharmaceutical technology. Background Technology

[0002] Polaprezinc is a novel anti-ulcer drug developed by Hamari New Drug Co., Ltd. of Japan, and is the first zinc-containing compound to be used clinically. Polaprezinc is generally prepared by chelating L-carnosine with zinc salt. Combining the advantages of L-carnosine and zinc, polaprezinc primarily targets gastric mucosal cells, possessing therapeutic and preventative effects against gastric ulcers.

[0003] Existing methods for preparing polyprezed zinc can be mainly broken down into the preparation of the intermediate L-carnosine, and the reaction of the intermediate L-carnosine with zinc salt to obtain the product polyprezed zinc.

[0004] 1. The preparation of the intermediate L-carnosine is currently mainly divided into chemical synthesis and biotechnological synthesis:

[0005] 1) The advantages of chemical synthesis are: the target product is synthesized through a predetermined route, and the types and amounts of impurities generated during the process are relatively stable. By adjusting the reaction conditions and purification methods, the impurity levels can be stably controlled, resulting in products that meet pharmaceutical quality standards. The disadvantages of chemical synthesis are: β-alanine and L-histidine, the main raw materials, are amphoteric compounds containing both amino and carboxyl groups, resulting in numerous reaction sites. Therefore, protecting groups need to be introduced during the preparation of L-carnosine to selectively protect these reaction sites. Since the protecting groups themselves do not enter the chemical structure of L-carnosine, the use of protecting groups, the reagents used to introduce protecting groups, the reagents used to remove protecting groups, and the corresponding time all increase the preparation cost.

[0006] 2) The advantages of biotechnology synthesis are: under certain conditions, the intermediate L-carnosine can be synthesized directly from β-alanine and L-histidine through microbial fermentation or bioenzymatic methods, saving the related costs of using protecting groups in chemical synthesis. The disadvantages of biotechnology synthesis are: the use of living cells in the microbial fermentation process leads to large fluctuations in the types, content and yield of impurities generated; for bioenzymatic methods, the current immobilized enzyme technology is in the transition stage from laboratory research and development to industrial application, the enzyme recycling process needs to be improved, and the obtained products are difficult to balance cost and quality.

[0007] The intermediate L-carnosine is a dipeptide compound with some water solubility, making it susceptible to microbial contamination during production, storage, transportation, and packaging. Its metabolites may affect the quality of the downstream product, polypyrene zinc. Corresponding solutions, such as adding antimicrobial agents to L-carnosine, establishing low-temperature storage facilities, and introducing sterilization equipment, will all further increase costs.

[0008] 2. Polyprezinc is prepared by reacting the intermediate L-carnosine with zinc salt. Currently, the main method used is chemical synthesis, which employs a polar solvent. L-carnosine is chelated with zinc salt, and the chelation product is precipitated due to its low solubility in the polar solvent.

[0009] Patent application CN111051289A discloses a method for synthesizing polypyrene zinc, using β-alanine and L-histidine as the main raw materials, each protected by a protecting group. For example: in step one, two methods are used to protect the amino group of β-alanine: ① protecting the amino group with a protecting group, involving protecting groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, trifluoroacetyl, tert-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, or formyl; ② protecting the amino group with phthalic anhydride; in step two, the carboxyl group, the nitrogen group on the imidazole group, and the amino group of L-histidine are protected; in step three, the intermediates from steps one and two are reacted; finally, in step four, the protecting group is removed to obtain the intermediate L-carnosine; in step five, L-carnosine reacts with zinc salt to obtain the target product, polypyrene zinc. The method described here uses protecting groups and certain groups in the intermediate structure obtained in step one, none of which constitute the skeletal structure of the target product. This necessitates the introduction and removal of protecting groups, resulting in waste of excipients and labor. The method for preparing a necessary intermediate described in this patent application involves using acyl chlorides and carboxylic acids, or triphosgene and carboxylic acids. While triphosgene is relatively stable, its application in production is prone to incomplete reactions, generating byproducts including phosgene (a highly toxic substance), placing high demands on production equipment, operational skills, and waste disposal. The method for preparing L-carnosine described in this patent involves: ① using hydrogen and a palladium catalyst under atmospheric or high pressure conditions not less than 0.1 MPa to reduce benzyloxycarbonyl or benzyl groups by heating. This reaction type is hydrogenation reduction, which places high demands on equipment in industrial production and requires safety assessments; ② using acids to remove various protecting groups. Differences in the selectivity of protecting group removal in this step can lead to incomplete removal and the generation of corresponding impurities. Furthermore, some fluorinated acids require equipment with high corrosion resistance. Using the above methods, the total yield of the target product, polyprezinc (L-carnosine zinc complex), was <87.8%.

[0010] Sifferd et al. (Reference: A New Synthesis of Carnosine, With Some Observation on the Splitting of the Benzil Group from Carbonobenzoky Derivatives and from Benzilthio Ethers) synthesized N-benzyloxycarbonyl-β-alanine from β-alanine. This N-benzyloxycarbonyl azide intermediate reacted with sodium nitrite, and then reacted with L-alanine methyl ester. Following hydrolysis and hydrogenation reduction, L-carnosine was obtained, which was then chelated with zinc salt to yield the product polypyrazine. This design approach generates an azide intermediate that is prone to explosion, making it unsuitable for large-scale production. Summary of the Invention

[0011] To address the shortcomings of existing technologies, this invention provides a method for preparing polyprezinc. The method employs a fully chemical synthesis process using inexpensive and readily available raw materials. The resulting polyprezinc product exhibits high purity, high yield, low raw material costs, low energy consumption, and low equipment requirements, making it suitable for industrial production.

[0012] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: a method for preparing polypyrene zinc, wherein the preparation method is as follows:

[0013] S1. Compound I and compound II react under alkaline conditions to prepare compound III;

[0014] The compound I is Compound II is Compound III is ;

[0015] S2. Under the action of a catalyst, compound III reacts with compound IV to prepare compound V;

[0016] The compound IV is The compound V is ;

[0017] S3 and compound V react with aldehydes and amine salts under the action of zinc salts. By controlling the pH of the reaction solution, compound VI is obtained, which is polypyrene zinc.

[0018] The compound VI is .

[0019] Further, the specific operation of step S1 is as follows: after mixing compound I, base and organic solvent evenly, reaction solution A is obtained; compound II is dissolved in organic solvent to obtain reaction solution B; reaction solution B is slowly added dropwise to reaction solution A to carry out the reaction, and the reaction temperature in the system is controlled to obtain compound III.

[0020] Furthermore, the base used in step S1 is at least one of triethylamine, pyridine, and N,N-diisopropylethylamine;

[0021] The organic solvent used in step S1 is at least one of acetonitrile, tetrahydrofuran, and dichloromethane;

[0022] The reaction temperature in step S1 is 0-5℃.

[0023] Furthermore, the specific operation of step S2 is as follows: at a certain temperature T2, the ligand, metal salt, reducing agent and compound IV are mixed in an organic solvent to prepare reaction solution C;

[0024] At a certain temperature T3, compound III is mixed with chlorosilane in an organic solvent, and then reaction solution D is prepared at a certain temperature T4.

[0025] At a certain temperature T5, reaction solution D is added dropwise to reaction solution C to carry out the reaction, and compound V is obtained.

[0026] Furthermore, in step S2, the organic solvent is at least one of tetrahydrofuran and 1,4-dioxane;

[0027] The ligand is at least one selected from 1,10-phenoroline, 2,9-dimethyl-1,10-phenoroline, and 2,2'-bipyridine;

[0028] The metal salt is nickel chloride hexahydrate;

[0029] The reducing agent is at least one of manganese and zinc;

[0030] The chlorosilane is at least one of trimethylchlorosilane and triethylchlorosilane;

[0031] The temperature T2 is 20-30℃; the temperature T3 is 0-10℃; the temperature T4 is 20-30℃; the temperature T5 is 20-30℃.

[0032] Furthermore, in step S2, the molar ratio of compound IV to the ligand is 1:(0.018-0.028).

[0033] The molar ratio of compound IV to the metal salt is 1:(0.012-0.016).

[0034] The molar ratio of compound IV to the reducing agent is 1:(2.0-2.2).

[0035] The molar ratio of compound IV to compound III is 1:(1.1-1.2).

[0036] The molar ratio of compound IV to chlorosilane is 1:(1.15-1.26).

[0037] The ligand and metal salt are added to the reaction, wherein the molar ratio of the ligand to the metal salt is (1.5-1.8):1.0.

[0038] Further, in step S3, the specific operations are as follows: compound V, sodium hydroxide, and organic solvent are mixed evenly to prepare reaction solution E; zinc salt is dissolved in organic solvent to prepare reaction solution F; at a certain temperature T6, reaction solution F is added dropwise to reaction solution E, and then the reaction is carried out at a certain temperature T7 to obtain transition intermediate X; then ammonium salt and aldehyde are added, and the reaction is carried out at a certain temperature T8 to obtain transition intermediate Y; finally, at a certain temperature T9, the pH of the reaction solution is adjusted to obtain the target product compound VI.

[0039] Furthermore, in step S3, the organic solvent is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide;

[0040] The zinc salt is zinc acetate dihydrate;

[0041] The ammonium salt is ammonium acetate and ammonium chloride;

[0042] The aldehyde is at least one of trioxymethylene and paraoxymethylene;

[0043] The temperature T6 is 10-20℃; the temperature T7 is 20-30℃; the temperature T8 is 60-70℃; and the temperature T9 is 5-15℃.

[0044] Furthermore, in step S3, the molar ratio of compound V to zinc acetate dihydrate is 1:(1.1-1.2).

[0045] The molar ratio of compound V to ammonium acetate is 1:(0.2-0.3), the molar ratio of compound V to ammonium chloride is 1:(0.8-0.9), and the molar ratio of ammonium acetate to ammonium chloride is 1.0:(2.5-3.2).

[0046] Furthermore, in step S3, the specific operation of adjusting the pH of the reaction solution is as follows: the reaction system is adjusted to pH < 2.5 using hydrochloric acid aqueous solution; then the pH of the reaction system is adjusted to 6.4-6.6 using sodium hydroxide aqueous solution.

[0047] The beneficial effects of this invention are:

[0048] 1) The preparation method described in this invention can effectively control impurities in each step by chemically synthesizing polyprezinc. The resulting polyprezinc product has a maximum single impurity content of ≤0.03% and a total impurity content of ≤0.1%. Its microbiological indicators meet the requirements of the Chinese Pharmacopoeia (CP2025), satisfying the high purity requirements for raw materials in the pharmaceutical technology field.

[0049] 2) The preparation method of polypyrene zinc described in this invention has a high yield, with a total yield >93.5%, and is suitable for industrial production.

[0050] 3) In the preparation method described in this invention, since no protecting group is used, the corresponding impurities generated by the introduction and removal of the protecting group are avoided, such as phthalimide derivative impurities, hydrazine, tert-butyloxycarbonyl derivative impurities, benzyl derivative impurities, fluorenemethyloxycarbonyl derivative impurities, etc.; thus saving the corresponding auxiliary materials and labor costs generated by the introduction and removal of the protecting group.

[0051] 4) The materials used in the preparation method described in this invention are inexpensive and readily available. The starting materials, reagents, and solvents are all commercially available bulk products with wide availability and sufficient supply, resulting in minimal pollution and environmental friendliness. L-serine is used as a raw material, and the price of commercially available bulk commodities is far lower than that of L-histidine and β-alanine.

[0052] 5) The preparation method of polypyrene zinc described in this invention has mild reaction conditions, no special requirements for production equipment, no need for special equipment that is resistant to high temperature and high pressure, and does not produce easily explosive materials such as azide intermediates during the preparation process. No additional third-party safety assessment is required, making it more versatile and suitable for industrial production.

[0053] 6) The polyprene zinc product prepared by the method described in this invention has elemental impurities and solvent residues that comply with ICH guidelines; microbiological test results comply with Chinese Pharmacopoeia standards; and stability test results show that the product has good stability. Attached Figure Description

[0054] Figure 1 HPLC chromatogram of polypyrimethanil zinc in Example 1;

[0055] Figure 2 To facilitate observation of impurities with low content Figure 1 Enlarged image;

[0056] Figure 3 The infrared detection spectrum of polypyriphos zinc in Example 1;

[0057] Figure 4 The H-NMR spectrum of polypyrimethanil in Example 1;

[0058] Figure 5The HPLC chromatogram of polypyrimethanil in Example 2;

[0059] Figure 6 To facilitate observation of impurities with low content Figure 5 Enlarged image;

[0060] Figure 7 The HPLC chromatogram of polypyrimethanil in Example 3;

[0061] Figure 8 To facilitate observation of impurities with low content Figure 7 Enlarged image. Detailed Implementation

[0062] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described in detail below. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0064] A method for preparing polypyrene zinc, wherein the preparation method comprises:

[0065] S1. Compound I and compound II react under alkaline conditions to prepare compound III;

[0066] The compound I is (L-serine), compound II is Compound III is ;

[0067] S2. Under the action of a catalyst, compound III reacts with compound IV to prepare compound V;

[0068] The compound IV is The compound V is ;

[0069] S3 and compound V react with aldehydes and amine salts under the action of zinc salts. By controlling the pH of the reaction solution, compound VI is obtained, which is polypyrene zinc.

[0070] The compound VI is Where n represents the repeating unit in the polymer structure.

[0071] Specifically, step S1 involves mixing compound I, the base, and the organic solvent to obtain reaction solution A; dissolving compound II in the organic solvent to obtain reaction solution B; and slowly adding reaction solution B to reaction solution A at a certain temperature T1 to obtain compound III.

[0072] Specifically, the base used in step S1 is at least one of triethylamine, pyridine, and N,N-diisopropylethylamine;

[0073] The organic solvent used in step S1 is at least one of acetonitrile, tetrahydrofuran, and dichloromethane;

[0074] The temperature T1 in step S1 is 0-5℃.

[0075] Specifically, step S2 involves mixing the ligand, metal salt, reducing agent, and compound IV in an organic solvent at a certain temperature T2 to prepare reaction solution C.

[0076] At a certain temperature T3, compound III is mixed with chlorosilane in an organic solvent, and then reaction solution D is prepared at a certain temperature T4.

[0077] At a certain temperature T5, reaction solution D is added dropwise to reaction solution C to carry out the reaction, and compound V is obtained.

[0078] Specifically, in step S2, the organic solvent is at least one of tetrahydrofuran and 1,4-dioxane;

[0079] The ligand is at least one selected from 1,10-phenoroline, 2,9-dimethyl-1,10-phenoroline, and 2,2'-bipyridine;

[0080] The metal salt is nickel chloride hexahydrate;

[0081] The reducing agent is at least one of manganese and zinc;

[0082] The chlorosilane is at least one of trimethylchlorosilane and triethylchlorosilane;

[0083] The temperature T2 is 20-30℃; the temperature T3 is 0-10℃; the temperature T4 is 20-30℃; the temperature T5 is 20-30℃.

[0084] Specifically, in step S2, the molar ratio of compound IV to the ligand is 1:(0.018-0.028).

[0085] The molar ratio of compound IV to the metal salt is 1:(0.012-0.016).

[0086] The molar ratio of compound IV to the reducing agent is 1:(2.0-2.2).

[0087] The molar ratio of compound IV to compound III is 1:(1.1-1.2).

[0088] The molar ratio of compound IV to chlorosilane is 1:(1.15-1.26).

[0089] The ligand and metal salt are added to the reaction, wherein the molar ratio of the ligand to the metal salt is (1.5-1.8):1.0.

[0090] Specifically, in step S3, the specific operations are as follows: compound V, sodium hydroxide, and organic solvent are mixed evenly to prepare reaction solution E; zinc salt is dissolved in organic solvent to prepare reaction solution F; at a certain temperature T6, reaction solution F is added dropwise to reaction solution E, and then the reaction is carried out at a certain temperature T7 to obtain transition intermediate X; then ammonium salt and aldehyde are added, and the reaction is carried out at a certain temperature T8 to obtain transition intermediate Y; finally, at a certain temperature T9, the pH of the reaction solution is adjusted to obtain the target product compound VI.

[0091] Among them, the transition intermediate X is The transition intermediate Y is .

[0092] Specifically, in step S3, the organic solvent is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide;

[0093] The zinc salt is zinc acetate dihydrate;

[0094] The ammonium salt is ammonium acetate and ammonium chloride;

[0095] The aldehyde is at least one of trioxymethylene and paraoxymethylene;

[0096] The temperature T6 is 10-20℃; the temperature T7 is 20-30℃; the temperature T8 is 60-70℃; and the temperature T9 is 5-15℃.

[0097] Specifically, in step S3, the molar ratio of compound V to zinc acetate dihydrate is 1:(1.1-1.2).

[0098] The molar ratio of compound V to ammonium acetate is 1:(0.2-0.3), the molar ratio of compound V to ammonium chloride is 1:(0.8-0.9), and the molar ratio of ammonium acetate to ammonium chloride is 1.0:(2.5-3.2).

[0099] Specifically, in step S3, the specific operation for adjusting the pH of the reaction solution is as follows: the reaction system is adjusted to pH < 2.5 using hydrochloric acid aqueous solution; then the pH of the reaction system is adjusted to 6.4-6.6 using sodium hydroxide aqueous solution.

[0100] More specifically, after the reaction in step S1 is completed, solid-liquid separation is performed. The separated solid is washed in water, then separated again and dried to obtain compound III.

[0101] In step S2, after the reaction is complete, the reaction solution is passed through a titanium rod filter and a filter cartridge in sequence, and some solvent is removed under reduced pressure. Then, water is added to perform solid-liquid separation. The separated solid is washed with purified water and dried to obtain compound V.

[0102] Step S3: After adjusting the pH, solid-liquid separation is performed. The separated solid is washed with purified water and dried to obtain compound VI (i.e., polyprezinc).

[0103] The raw material compound II (acetyl chloride) involved in the embodiments of the present invention can be obtained by the following conventional method: using acetic acid as raw material, the carboxyl group is chlorinated with chlorination reagents such as thionyl chloride, oxalyl chloride, phosphorus trichloride, etc. to obtain acetyl chloride.

[0104] The specific preparation process of thionyl chloride, using one of the chlorination reagents, is as follows:

[0105] ;

[0106] Add 6.0 kg of acetic acid to a glass-lined reactor, purge with nitrogen until the oxygen content is ≤6%, and then purge with nitrogen for protection. Add 8.5 kg of dichloromethane and 14.3 kg of thionyl chloride to the reactor, stir at 30-35℃ for 1 h, add 0.08 kg of N,N-dimethylformamide dropwise, continue stirring at this temperature for 3 h, remove the solvent under reduced pressure to obtain 7.9 kg of acetyl chloride, which is then stored in the reactor for later use.

[0107] Example 1

[0108] A method for preparing polypyrene zinc is as follows:

[0109] Preparation of S1 and Compound III:

[0110] 9.57 kg of L-serine was added to a glass-lined reactor, and nitrogen was used to purge until the oxygen content was ≤6%, with continuous nitrogen purging for protection. Then, 28.7 kg of acetonitrile and 9.7 kg of triethylamine were added, and the mixture was stirred until all the solids were dissolved, yielding reaction solution A. 19.1 kg of acetonitrile was added to the glass-lined reactor containing the acetyl chloride to be used in Synthesis Example 1, and the mixture was stirred until homogeneous, yielding reaction solution B. The reactor temperature was controlled at 0-5℃, and reaction solution B was added dropwise to reaction solution A. After the addition was complete, the mixture was stirred at 0-5℃ for 2 hours, centrifuged, filtered, and the filter cake was returned to the reactor. 30 kg of drinking water was added, and the mixture was stirred at 0-5℃ for 1 hour, centrifuged, filtered, and dried to obtain 15.61 kg of compound III, with a yield of 99.5% and a purity of 99.6%.

[0111] Preparation of S2 and compound V:

[0112] Add 33.1 kg of tetrahydrofuran to glass-lined reactor #1. Purge the air from the stainless steel reactor with nitrogen until the oxygen content in the solvent is ≤5 mg / L, and continue to purge with nitrogen for protection. Using a closed feeder, add 0.24 kg of 1,10-phenanthroline and 0.21 kg of nickel chloride hexahydrate to the reactor, controlling the reactor temperature at 20-25℃ and stirring for 1 hour. Using a closed feeder, add 8.25 kg of manganese powder and 11.03 kg of 4-bromo-1H imidazole to the reactor, stirring for 1 hour to prepare reaction solution C, which is then stored in the reactor for later use. Add 22.1 kg of tetrahydrofuran to glass-lined reactor #2. Purge the air from the stainless steel reactor with nitrogen until the oxygen content in the solvent is ≤5 mg / L, and continue to purge with nitrogen for protection. Using a closed feeder, 15.5 kg of compound III was added to the reactor. While maintaining the reactor temperature at 0-5℃, 10.27 kg of trimethylchlorosilane was added dropwise. After the addition was complete, the reactor temperature was raised to 20-25℃ and stirred for 1 hour to prepare reaction solution D. Maintaining the temperature of reactor #1 at 20-25℃, reaction solution D was added dropwise to reaction solution C, and the mixture was stirred for 7 hours after the addition was complete. The mixture was then filtered sequentially through a titanium rod filter and a cartridge filter into a glass-lined reactor #3. The bath temperature was maintained below 50℃, and the solvent was removed under reduced pressure. The mixture was concentrated to a total weight of approximately 30 kg. 50 kg of purified water was added dropwise to the system, and the mixture was stirred for 2 hours after the addition was complete. The mixture was then discharged into a centrifuge for filtration, washed with purified water, and dried to obtain 14.75 kg of compound V, with a yield of 99.7% and a purity of 99.3%.

[0113] S3, Preparation of Compound VI:

[0114] Add 14.6 kg of compound V and 2.96 kg of sodium hydroxide to glass-lined reactor #1. Purge with nitrogen until the oxygen content is ≤6%, and continue purging with nitrogen for protection. Add 21.9 kg of N,N-dimethylformamide to the reactor, and stir for 1 hour to obtain reaction solution E. Add 17.87 kg of zinc acetate dihydrate to stainless steel reactor #2. Purge with nitrogen until the oxygen content is ≤6%, and continue purging with nitrogen for protection. Add 21.9 kg of N,N-dimethylformamide to the reactor, and stir for 0.5 hours to obtain reaction solution F. Controlling the temperature of reactor #1 at 10-15℃, reaction solution F is added dropwise to reaction solution E. After the addition is complete, the reactor temperature is raised to 25-30℃ and stirred for 2 hours. 1.43 kg ammonium acetate, 3.17 kg ammonium chloride, and 2.33 kg paraformaldehyde are added to the reactor. After the addition is complete, the reactor temperature is raised to 60-65℃ and the reaction is maintained at this temperature for 10 hours. After the reaction is complete, the reactor temperature is lowered to 5-10℃, and hydrochloric acid aqueous solution is added dropwise to adjust the pH of the reaction solution to 2.3-2.5. After the addition is complete, the mixture is stirred for 0.5 hours. Controlling the reactor temperature at 5-10℃, sodium hydroxide aqueous solution is added dropwise to adjust the pH of the reaction solution to 6.4-6.6. After the addition is complete, the reactor temperature is controlled at 5-10℃ and the mixture is stirred for 3 hours. The mixture is then discharged into a centrifuge for filtration. The filter cake is washed with purified water and dried to obtain 20.32 kg of compound VI, with a yield of 94.8% and a purity of 99.9%.

[0115] The HPLC chromatogram of polypyrene zinc is as follows: Figure 1 , Figure 2 As shown in Table 1, the HPLC detection chromatogram data are as follows.

[0116] Table 1. HPLC chromatogram data of polypyrimethanil in Example 1

[0117]

[0118] The infrared detection spectrum of polypyrene zinc is as follows: Figure 3 As shown, the H-NMR spectrum of polypyrene zinc is as follows: Figure 4 As shown. The test conditions for the H-NMR detection spectrum are as follows:

[0119] Acquisition time: 2.441 seconds;

[0120] Data points: 32768;

[0121] Solvent: Deuterated heavy water;

[0122] Delay time: 10.000 seconds

[0123] Spectral width: 6713.1 Hz;

[0124] Transmit power: 62 Hz

[0125] Spectrometer frequency: 599.777 MHz.

[0126] The downstream formulations of polyprene zinc are granules or orally disintegrating tablets, both of which are oral solid dosage forms. Therefore, elemental impurities in the polyprene zinc prepared in this example were determined, with limits based on ICH Q3D(R2): Elemental Impurities Guidelines. The elemental impurity details are shown in Table 2 below.

[0127] Table 2 Elemental impurities in polypyrene zinc prepared in Example 1

[0128]

[0129] The test results show that the preparation method described in this invention has a good control effect on the active use of nickel and other elemental impurities that require evaluation.

[0130] The solvent residue of the polypyrene zinc prepared in this example was determined according to the ICH Q3C(R9): Impurities: Residual Solvents Guideline. The specific results are shown in Table 3 below.

[0131] Table 3 Solvent residues in polypyrazine zinc prepared in Example 1

[0132]

[0133] Stability tests were conducted on the polypred zinc prepared in this embodiment. The experimental conditions were established in accordance with the ICH Tripartite Harmonized Guidelines for the Stability Testing of New Drug Substances and Formulations Q1A(R2) 2.1.2 Strength Test. The specific results are shown in Table 4 below.

[0134] Table 4. Stability test of polypyridine zinc prepared in Example 1

[0135]

[0136] Experimental results show that the polyprene zinc prepared by the method described in this invention still has good stability even under relatively harsh conditions.

[0137] Referring to the Chinese Pharmacopoeia CP2025 edition, General Chapter 1107 "Microbial Limits for Non-sterile Drugs", microbial experiments were conducted on the polypred zinc prepared in this example, and the specific results are shown in Table 5 below.

[0138] Table 5. Microbiological detection results of polypyriphos zinc prepared in Example 1

[0139]

[0140] Example 2

[0141] A method for preparing polypyrene zinc is as follows:

[0142] Preparation of S1 and Compound III:

[0143] 9.57 kg of L-serine was added to a glass-lined reactor, and nitrogen was used to purge until the oxygen content was ≤6%, with continuous nitrogen purging for protection. Then, 28.7 kg of tetrahydrofuran and 7.56 kg of pyridine were added, and the mixture was stirred until all the solids dissolved, yielding reaction solution A. 19.1 kg of acetonitrile was added to the glass-lined reactor containing the acetyl chloride from Synthesis Example 1, and the mixture was stirred until homogeneous, yielding reaction solution B. The reactor temperature was controlled at 0-5℃, and reaction solution B was added dropwise to reaction solution A. After the addition was complete, the mixture was stirred at 0-5℃ for 2 hours, centrifuged, filtered, and the filter cake was returned to the reactor. 30 kg of drinking water was added, and the mixture was stirred at 0-5℃ for 1 hour, centrifuged, filtered, and dried to obtain 15.60 kg of compound III, with a yield of 99.6% and a purity of 99.5%.

[0144] Preparation of S2 and compound V:

[0145] Add 34.4 kg of 1,4-dioxane to glass-lined reactor #1. Purge the air from the stainless steel reactor with nitrogen until the oxygen content in the solvent is ≤5 mg / L, and continue to purge with nitrogen for protection. Using a closed feeder, add 0.36 kg of 2,9-dimethyl-1,10-phenanthroline and 0.25 kg of nickel chloride hexahydrate to the reactor, controlling the reactor temperature at 25-30℃ and stirring for 1 hour. Using a closed feeder, add 8.66 kg of manganese powder and 11.47 kg of 4-bromo-1H imidazole to the reactor, stirring for 1 hour to prepare reaction solution C, which is then stored in the reactor for later use. Add 23.0 kg of 1,4-dioxane to glass-lined reactor #2. Purge the air from the stainless steel reactor with nitrogen until the oxygen content in the solvent is ≤5 mg / L, and continue to purge with nitrogen for protection. Using a closed feeder, 15.45 kg of compound III was added to the reactor. While maintaining the reactor temperature at 0-5℃, 14.21 kg of trimethylchlorosilane was added dropwise. After the addition was complete, the reactor temperature was raised to 25-30℃ and stirred for 1 hour to prepare reaction solution D. Maintaining the temperature of reactor #1 at 25-30℃, reaction solution D was added dropwise to reaction solution C, and the mixture was stirred for 7 hours after the addition was complete. The mixture was then filtered sequentially through a titanium rod filter and a cartridge filter into a glass-lined reactor #3. The bath temperature was maintained below 50℃, and the solvent was removed under reduced pressure. The mixture was concentrated to a total weight of approximately 30 kg. 50 kg of purified water was added dropwise to the system, and the mixture was stirred for 2 hours after the addition was complete. The mixture was then discharged into a centrifuge for filtration, washed with purified water, and dried to obtain 15.32 kg of compound V, with a yield of 99.5% and a purity of 99.4%.

[0146] S3, Preparation of Compound VI:

[0147] Add 15.22 kg of compound V and 3.09 kg of sodium hydroxide to glass-lined reactor #1. Purge with nitrogen until the oxygen content is ≤6%, and continue purging with nitrogen for protection. Add 21.9 kg of N,N-dimethylacetamide to the reactor, and stir for 1 hour after addition to obtain reaction solution E. Add 19.48 kg of zinc acetate dihydrate to stainless steel reactor #2. Purge with nitrogen until the oxygen content is ≤6%, and continue purging with nitrogen for protection. Add 21.9 kg of N,N-dimethylacetamide to the reactor, and stir for 0.5 hours after addition to obtain reaction solution F. Controlling the temperature of reactor #1 at 15-20℃, reaction solution F is added dropwise to reaction solution E. After the addition is complete, the reactor temperature is raised to 25-30℃ and stirred for 2 hours. 1.78 kg ammonium acetate, 3.51 kg ammonium chloride, and 2.55 kg paraformaldehyde are added to the reactor. After the addition is complete, the reactor temperature is raised to 65-70℃ and the reaction is maintained at this temperature for 12 hours. After the reaction is complete, the reactor temperature is lowered to 5-10℃, and hydrochloric acid aqueous solution is added dropwise to adjust the pH of the reaction solution to 2.3-2.5. After the addition is complete, the mixture is stirred for 0.5 hours. Controlling the reactor temperature at 5-10℃, sodium hydroxide aqueous solution is added dropwise to adjust the pH of the reaction solution to 6.4-6.6. After the addition is complete, the reactor temperature is controlled at 5-10℃ and the mixture is stirred for 3 hours. The mixture is then discharged into a centrifuge for filtration. The filter cake is washed with purified water and dried to obtain 21.14 kg of compound VI, with a yield of 94.6% and a purity of 99.9%.

[0148] HPLC detection chromatogram as follows Figure 5 , Figure 6 As shown in Table 6, the HPLC detection chromatogram data are as follows.

[0149] Table 6. HPLC chromatogram data of polypyrimethanil in Example 2

[0150]

[0151] Elemental impurities in the polymethyl methacrylate zinc prepared in this embodiment were determined according to ICH Q3D(R2): Elemental Impurities Guidelines. The elemental impurity details are shown in Table 7 below.

[0152] Table 7 Elemental impurities in polypyrene zinc prepared in Example 2

[0153]

[0154] The test results show that the preparation method described in this invention has a good control effect on the active use of nickel and other elemental impurities that require evaluation.

[0155] The solvent residue of the polypyrene zinc prepared in this example was determined according to the ICH Q3C(R9): Impurities: Residual Solvents Guideline. The specific results are shown in Table 8 below.

[0156] Table 8 Solvent residues in polypyridine zinc prepared in Example 2

[0157]

[0158] Stability tests were conducted on the polypred zinc prepared in this embodiment. The experimental conditions were established in accordance with the ICH Tripartite Harmonized Guidelines for the Stability Testing of New Drug Substances and Formulations Q1A(R2) 2.1.2 Strength Test. The specific results are shown in Table 9 below.

[0159] Table 9. Stability test of polypyridine zinc prepared in Example 2

[0160]

[0161] Experimental results show that the polyprene zinc prepared by the method described in this paper still has good stability even under relatively harsh conditions.

[0162] Referring to the Chinese Pharmacopoeia CP2025 edition, General Chapter 1107 "Microbial Limits for Non-sterile Drugs", microbial experiments were conducted on the polypred zinc prepared in this example, and the specific results are shown in Table 10 below.

[0163] Table 10 Microbiological detection results of polypyrene zinc prepared in Example 2

[0164]

[0165] Example 3

[0166] A method for preparing polypyrene zinc is as follows:

[0167] Preparation of S1 and Compound III:

[0168] 9.57 kg of L-serine was added to a glass-lined reactor, and nitrogen was used to purge until the oxygen content was ≤6%, with continuous nitrogen protection. Then, 28.7 kg of dichloromethane and 12.4 kg of N,N-diisopropylethylamine were added, and the mixture was stirred until all the solids were dissolved, yielding reaction solution A. 19.1 kg of dichloromethane was added to the glass-lined reactor containing the acetyl chloride from Synthesis Example 1, and the mixture was stirred until homogeneous, yielding reaction solution B. The reactor temperature was controlled at 0-5℃, and reaction solution B was added dropwise to reaction solution A. After the addition was complete, the mixture was stirred at 0-5℃ for 2 hours, centrifuged, filtered, and the filter cake was returned to the reactor. 30 kg of drinking water was added, and the mixture was stirred at 0-5℃ for 1 hour, centrifuged, filtered, and dried to obtain 15.59 kg of compound III, with a yield of 99.5% and a purity of 99.5%.

[0169] Preparation of S2 and compound V:

[0170] Add 36.1 kg of tetrahydrofuran to glass-lined reactor #1. Purge the air from the stainless steel reactor with nitrogen until the oxygen content in the solvent is ≤5 mg / L, and continue to purge with nitrogen for protection. Using a closed feeder, add 0.33 kg of 2,2'-bipyridine and 0.29 kg of nickel chloride hexahydrate to the reactor, controlling the reactor temperature at 20-25℃, and stir for 1 hour. Using a closed feeder, add 10.8 kg of zinc powder and 12.03 kg of 4-bromo-1H imidazole to the reactor, and stir for 1 hour to prepare reaction solution C, which is then stored in the reactor for later use. Add 24.1 kg of tetrahydrofuran to glass-lined reactor #2. Purge the air from the stainless steel reactor with nitrogen until the oxygen content in the solvent is ≤5 mg / L, and continue to purge with nitrogen for protection. Using a closed feeder, 15.5 kg of compound III was added to the reactor. While maintaining the reactor temperature at 0-5℃, 10.27 kg of trimethylchlorosilane was added dropwise. After the addition was complete, the reactor temperature was raised to 25-30℃ and stirred for 1 hour to prepare reaction solution D. Maintaining the temperature of reactor #1 at 25-30℃, reaction solution D was added dropwise to reaction solution C, and the mixture was stirred for 9 hours after the addition was complete. The mixture was then filtered sequentially through a titanium rod filter and a cartridge filter into a glass-lined reactor #3. The bath temperature was maintained below 50℃, and the solvent was removed under reduced pressure. The mixture was concentrated to a total weight of approximately 30 kg. 50 kg of purified water was added dropwise to the system, and the mixture was stirred for 2 hours after the addition was complete. The mixture was then discharged into a centrifuge for filtration, washed with purified water, and dried to obtain 16.06 kg of compound V, with a yield of 99.5% and a purity of 99.5%.

[0171] S3, Preparation of Compound VI:

[0172] Add 16.0 kg of compound V and 3.24 kg of sodium hydroxide to a glass-lined reactor (No. 1). Purge with nitrogen until the oxygen content is ≤6%, and continue purging with nitrogen for protection. Add 21.9 kg of dimethyl sulfoxide to the reactor, and stir for 1 hour to obtain reaction solution E. Add 21.37 kg of zinc acetate dihydrate to a stainless steel reactor (No. 2). Purge with nitrogen until the oxygen content is ≤6%, and continue purging with nitrogen for protection. Add 21.9 kg of dimethyl sulfoxide to the reactor, and stir for 0.5 hours to obtain reaction solution F. Controlling the temperature of reactor #1 at 15-20℃, reaction solution F is added dropwise to reaction solution E. After the addition is complete, the reactor temperature is raised to 20-25℃ and stirred for 2 hours. Then, 2.19 kg of ammonium acetate, 3.91 kg of ammonium chloride, and 2.56 kg of paraformaldehyde are added to the reactor. After the addition is complete, the reactor temperature is raised to 60-65℃ and the reaction is maintained at this temperature for 11 hours. After the reaction is complete, the reactor temperature is lowered to 5-10℃, and hydrochloric acid aqueous solution is added dropwise to adjust the pH of the reaction solution to 2.3-2.5. After the addition is complete, the mixture is stirred for 0.5 hours. Controlling the reactor temperature at 5-10℃, sodium hydroxide aqueous solution is added dropwise to adjust the pH of the reaction solution to 6.4-6.6. After the addition is complete, the reactor temperature is controlled at 5-10℃ and the mixture is stirred for 3 hours. The mixture is then discharged into a centrifuge for filtration. The filter cake is washed with purified water and dried to obtain 22.28 kg of compound VI, with a yield of 94.9% and a purity of 99.9%.

[0173] HPLC detection chromatogram as follows Figure 7 , Figure 8 As shown in Table 11, the HPLC detection chromatogram data are as follows.

[0174] Table 11 HPLC chromatogram data of polypyrimethanil in Example 3

[0175]

[0176] Elemental impurities in the polymethyl methacrylate zinc prepared in this embodiment were determined, with limits based on ICH Q3D(R2): Elemental Impurities Guidelines. The elemental impurity details are shown in Table 12 below.

[0177] Table 12 Elemental impurities in polypyrene zinc prepared in Example 3

[0178]

[0179] The test results show that the preparation method described in this invention has a good control effect on the active use of nickel and other elemental impurities that require evaluation.

[0180] The solvent residue of the polypyrene zinc prepared in this example was determined according to the ICH Q3C(R9): Impurities: Residual Solvents Guideline. The specific results are shown in Table 13 below.

[0181] Table 13 Solvent residues in polypyrazine zinc prepared in Example 3

[0182]

[0183] Stability tests were conducted on the polypred zinc prepared in this embodiment. The experimental conditions were established in accordance with the ICH Tripartite Harmonized Guidelines, Stability Testing of New Drug Substances and Formulations Q1A(R2) 2.1.2 Strength Test. The specific results are shown in Table 14 below.

[0184] Table 14 Stability test of polypyridine zinc prepared in Example 3

[0185]

[0186] Experimental results show that the polyprene zinc prepared by the method described in this paper still has good stability even under relatively harsh conditions.

[0187] Referring to the Chinese Pharmacopoeia CP2025 edition, General Chapter 1107 "Microbial Limits for Non-sterile Drugs", microbial experiments were conducted on the polypred zinc prepared in this example, and the specific results are shown in Table 15 below.

[0188] Table 15 Microbiological detection results of polypyriphos zinc prepared in Example 3

[0189]

[0190] Comparative Example 1

[0191] Compound III was prepared using the same method as in Example 1, except that in step S1, reaction solution A was added dropwise to reaction solution B (unlike in this invention where reaction solution B is added dropwise to reaction solution A). The purity of compound III prepared using this comparative example decreased from 99.6% to 77.3%. Changing the feeding method to achieve a localized excess of acyl chloride led to dehydration with the carboxylic acid to form an anhydride, which then reacted with the primary amine of L-serine that had not participated in the condensation reaction, generating the corresponding dipeptide or polypeptide derivative. This resulted in a decrease in the purity of compound III, severely affecting subsequent reactions.

[0192] Comparative Example 2

[0193] Compound III was prepared using the same method as in Example 1, except that in step S1, when reaction solution B was added dropwise to reaction solution A, the temperature T1 of the reaction solution was controlled to be -10 to 0°C (lower than the temperature specified in this invention). Compound IV prepared using this comparative example had a yield of 99.4% and a purity of 99.5%. Compared to Example 1, there was no significant change in yield and purity. However, lowering the reaction temperature requires a lower-temperature condensing medium and a longer cooling time, resulting in a waste of energy and time.

[0194] Comparative Example 3

[0195] Compound III was prepared using the same method as in Example 1, except that in step S1, reaction solution B was added dropwise to reaction solution A, and the temperature T1 of the reaction solution was controlled at 15 to 25°C (higher than the temperature specified in this invention). The purity of compound III prepared using this comparative example was 95.1%. As the reaction temperature increased, the activity of acetyl chloride increased significantly, reacting with multiple sites of L-serine, leading to a decrease in the purity of compound III.

[0196] The relevant conditions and product data for Comparative Examples 1-3 and Example 1 are shown in Table 16 below.

[0197] Table 16. Investigation of factors affecting the yield and purity of compound III in step S1

[0198]

[0199] Comparative Example 4

[0200] Compound V was prepared using the same method as in Example 1, except that in step S2, the temperature T5 of the reaction solution was controlled at 0-10°C (lower than the temperature specified in this invention) when reaction solution D was added dropwise to reaction solution C, and after the dropwise reaction was completed. Using this comparative preparation method, the reaction completion time was monitored for 20 hours, indicating that decreasing the reaction temperature significantly affected the reaction rate. The purity of the product compound V was 97.6%, and the impurity level tended to increase with prolonged reaction time.

[0201] Comparative Example 5

[0202] Compound V was prepared using the same method as in Example 1, except that in step S2, the temperature T5 of the reaction solution was controlled at 40-50°C (higher than the temperature specified in this invention) when reaction solution D was added dropwise to reaction solution C and after the dropwise reaction was completed. Using this comparative preparation method, the purity of compound V obtained was 96.9%, with a significantly increased impurity level.

[0203] The relevant conditions and product data for Comparative Examples 4, 5 and Example 1 are shown in Table 17 below.

[0204] Table 17 Effect of reaction temperature in step S2 on the yield and purity of compound V

[0205]

[0206] Comparative Example 6

[0207] Compound V was prepared using the same method as in Example 1, except that in step S2, the molar ratio of manganese powder as reducing agent to the molar amount of compound IV was 1.6 (lower than the limit of this invention), the reaction time was monitored for 10 h, and the reaction rate decreased; the yield of product compound V was 82.3%, which was significantly lower; the impurity level increased, and the purity was 98.4%.

[0208] Comparative Example 7

[0209] Compound V was prepared using the same method as in Example 1, except that in step S2, the molar ratio of manganese powder as a reducing agent relative to the molar amount of compound IV was 2.6 (higher than the limit of this invention). The yield of product compound V was 99.8%, with no significant change; the purity was 98.9%, with an increasing trend in impurity levels.

[0210] The relevant conditions and product data for Comparative Examples 6, 7 and Example 1 are shown in Table 18 below.

[0211] Table 18 Effect of reducing agent dosage in step S2 on the yield and purity of compound V

[0212]

[0213] Comparative Example 8

[0214] Compound V was prepared using the same method as in Example 1, except that in step S2, the molar ratio of compound III to compound IV was 1.5 (higher than the limit of this invention). The reaction could proceed normally, but the resulting compound V contained a large amount of compound III, which seriously affected the product quality when carried into step S3.

[0215] Comparative Example 9

[0216] Compound V was prepared using the same method as in Example 1, except that in step S2, the molar ratio of the ligand to the metal salt relative to the molar amount of compound IV was 1.0:1.0 (different from the limitation of this invention), and the reaction completion time was detected at 15 h, showing a significant decreasing trend in the reaction rate. The yield of product compound V was 96.8%, showing a decreasing trend, while the purity was 99.0%, with no significant change.

[0217] Comparative Example 10

[0218] Compound V was prepared using the same method as in Example 1, except that in step S2, the molar ratio of ligand to metal salt relative to the molar amount of compound IV was 2.4:1.0 (different from the limitation of this invention), and the reaction completion time was detected to be 13 h, showing a significant decreasing trend in reaction rate. The yield of product compound V was 99.7%, and the purity was 99.1%, with no significant changes.

[0219] The relevant conditions and product data for Comparative Examples 9, 10 and Example 1 are shown in Table 19 below.

[0220] Table 19 Effect of ligand and metal salt in step S2 on the yield and purity of compound V

[0221]

[0222] Comparative Example 11

[0223] Compound V was prepared using the same method as in Example 1, except that in step S2, the molar ratio of chlorosilane to the molar amount of compound IV was 0.80 (lower than the limit of this invention), and the reaction was detected after more than 24 hours, with a large amount of raw materials still remaining.

[0224] Comparative Example 12

[0225] Compound V was prepared using the same method as in Example 1, except that in step S2, the molar ratio of chlorosilane to compound IV was 1.60 (higher than the limit of this invention), and the purity of product compound V was 71.6%, with a significant increase in impurity levels.

[0226] The relevant conditions and product data for Comparative Examples 11, 12 and Example 1 are shown in Table 20 below.

[0227] Table 20 Effect of the amount of chlorosilane added in step S2 on the yield and purity of compound V

[0228]

[0229] Comparative Example 13

[0230] Compound VI was prepared using the same method as in Example 1, except that in step S3, when the transition intermediate X was obtained, the reaction system temperature T6 was controlled at 0-5℃ (lower than the limit of this invention). The yield of product compound VI was 94.3%, and the purity was 99.8%, with no significant change. However, lowering the reaction temperature required a condensing medium with a lower temperature and a longer cooling time, resulting in a waste of energy and time.

[0231] Comparative Example 14

[0232] Compound VI was prepared using the same method as in Example 1, except that in step S3, when the transition intermediate X was obtained, the reaction system temperature T6 was controlled at 25-35℃ (higher than the limit of this invention). The purity of the product compound VI was 97.4%, and the impurity level was significantly increased, which did not meet the product quality standards.

[0233] The relevant conditions and product data for Comparative Examples 13, 14 and Example 1 are shown in Table 21 below.

[0234] Table 21 Effect of reaction temperature T6 controlled in step S3 on the yield and purity of compound VI

[0235]

[0236] Comparative Example 15

[0237] Compound VI was prepared using the same method as in Example 1, except that in step S3, when the transition intermediate X was obtained, the reaction system temperature T7 was controlled at 0-10°C (lower than the limit of this invention). It was detected that after more than 24 hours of reaction, a large amount of raw materials had not reacted completely, and the reaction could not continue.

[0238] Comparative Example 16

[0239] Compound VI was prepared using the same method as in Example 1, except that in step S3, when the transition intermediate X was obtained, the reaction system temperature T7 was controlled at 40-50℃ (higher than the limit of this invention). The purity of the product compound VI was 98.7%, but the impurity level increased, which did not meet the product quality standards.

[0240] The relevant conditions and product data for Comparative Examples 15, 16 and Example 1 are shown in Table 22 below.

[0241] Table 22 Effect of reaction temperature T7 controlled in step S3 on the yield and purity of compound VI

[0242]

[0243] Comparative Example 17

[0244] Compound VI was prepared using the same method as in Example 1, except that in step S3, when the transition intermediate Y was obtained, the reaction system temperature T8 was controlled at 40-50°C (lower than the limit of this invention). It was detected that after more than 24 hours of reaction, a large amount of raw materials had not reacted completely, and the reaction could not continue.

[0245] Comparative Example 18

[0246] Compound VI was prepared using the same method as in Example 1, except that in step S3, when the transition intermediate Y was obtained, the reaction system temperature T8 was controlled at 80-90℃ (higher than the limit of this invention). As a result, the impurity level in the product compound VI increased and did not meet the product quality standards.

[0247] The relevant conditions and product data for Comparative Examples 17, 18 and Example 1 are shown in Table 23 below.

[0248] Table 23 Effect of reaction temperature T8 controlled in step S3 on the yield and purity of compound VI

[0249]

[0250] Comparative Example 19

[0251] Compound VI was prepared using the same method as in Example 1, except that in step S3, when adjusting the pH of the prepared compound VI, the reaction system temperature T9 was controlled to be -5 to 5°C (lower than the limit of this invention). The yield of product compound VI was 94.3%, and the purity was 99.9%, with no significant change. However, lowering the reaction temperature required a condensing medium with a lower temperature and a longer cooling time, resulting in a waste of energy and time.

[0252] Comparative Example 20

[0253] Compound VI was prepared using the same method as in Example 1, except that in step S3, when adjusting the pH of the prepared compound VI, the reaction system temperature T9 was controlled at 20-30℃ (higher than the limit of this invention). As a result, the impurity level in the product compound VI increased, and the purity did not meet the product quality standards.

[0254] The relevant conditions and product data for Comparative Examples 19, 20 and Example 1 are shown in Table 24 below.

[0255] Table 24 Effect of reaction temperature T9 controlled in step S3 on the yield and purity of compound VI

[0256]

[0257] Comparative Example 21

[0258] Compound VI was prepared using the same method as in Example 1, except that in step S3, the molar ratio of zinc acetate dihydrate added to the reaction relative to the molar amount of compound V was 0.800 (lower than the limit of this invention). The yield of product compound VI was 66.3%, the impurity level increased, and the purity did not meet the quality standards.

[0259] Comparative Example 22

[0260] Compound VI was prepared using the same method as in Example 1, except that in step S3, the molar ratio of zinc acetate dihydrate to compound V was 1.500 (higher than the limit of this invention). After monitoring the reaction for more than 24 hours, a large amount of raw materials were still not completely reacted, and the reaction could not continue.

[0261] The relevant conditions and product data for Comparative Examples 21, 22 and Example 1 are shown in Table 25 below.

[0262] Table 25 Effect of the amount of zinc acetate dihydrate added in step S3 on the yield and purity of compound VI

[0263]

[0264] Comparative Example 23

[0265] Compound VI was prepared using the same method as in Example 1, except that in step S3, the molar ratio of ammonium acetate to ammonium chloride added to the reaction was 1.0:1.0 relative to the molar amount of compound V (different from the 1.0:2.5-3.2 limit of this invention). After monitoring the reaction for more than 24 hours, a large amount of raw materials were still not completely reacted, and the reaction could not continue.

[0266] Comparative Example 24

[0267] Compound VI was prepared using the same method as in Example 1, except that in step S3, the molar ratio of ammonium acetate to ammonium chloride added to the reaction was 1.0:5.0 relative to the molar amount of compound V (different from the 1.0:2.5-3.2 limit of this invention). The impurity level of product compound VI was significantly increased, and its purity did not meet the quality standards.

[0268] The relevant conditions and product data for Comparative Examples 23, 24 and Example 1 are shown in Table 26 below.

[0269] Table 26 Effect of the molar ratio of ammonium chloride to ammonium acetate in step S3 on the yield and purity of compound VI

[0270]

[0271] Comparative Example 25

[0272] Compound VI was prepared using the same method as in Example 1, except that in step S3, when adjusting the pH of the prepared compound VI, hydrochloric acid was used to adjust the pH of the system to 5.0-5.5 (higher than the limit of this invention), resulting in a yield of 65.4% for the product compound VI, which was significantly reduced.

[0273] Comparative Example 26

[0274] Compound VI was prepared using the same method as in Example 1, except that in step S3, when adjusting the pH of the prepared compound VI, sodium hydroxide was used to adjust the pH of the system to 4.0-4.5 (lower than the limit of this invention), resulting in a product compound VI yield of 57.6%, which is a significant decrease in yield.

[0275] Comparative Example 27

[0276] Compound VI was prepared using the same method as in Example 1, except that in step S3, when adjusting the pH of the prepared compound VI, sodium hydroxide was used to adjust the pH of the system to 9.0-9.5 (higher than the limit of this invention), and the yield of product compound VI was 95.5%, but the zinc salt content in the product did not meet the quality standard.

[0277] The relevant conditions and product data for Comparative Examples 25-27 and Example 1 are shown in Table 27 below.

[0278] Table 27 Effect of pH of reaction solution in step S3 on the yield and purity of compound VI

[0279]

[0280] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0281] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method of preparing polaprezinc, characterized by, The preparation method is as follows: S1. After mixing compound I, the base and the organic solvent evenly, reaction solution A is obtained; compound II is dissolved in the organic solvent to obtain reaction solution B; reaction solution B is slowly added dropwise to reaction solution A to carry out the reaction, and the reaction temperature in the system is controlled to obtain compound III. The compound I is Compound II is Compound III is ; S2. At a certain temperature T2, the ligand, metal salt, reducing agent and compound IV are mixed in an organic solvent to prepare reaction solution C; at a certain temperature T3, compound III and chlorosilane are mixed in an organic solvent, and then at a certain temperature T4, reaction solution D is prepared; at a certain temperature T5, reaction solution D is added dropwise to reaction solution C to react and obtain compound V. The compound IV is , the compound V is ; The ligand is at least one selected from 1,10-phenoroline, 2,9-dimethyl-1,10-phenoroline, and 2,2'-bipyridine; The metal salt is nickel chloride hexahydrate; The reducing agent is at least one of manganese and zinc; The chlorosilane is at least one of trimethylchlorosilane and triethylchlorosilane; The temperature T2 is 20-30℃; the temperature T3 is 0-10℃; the temperature T4 is 20-30℃; the temperature T5 is 20-30℃; S3. Compound V, sodium hydroxide, and organic solvent are mixed evenly to prepare reaction solution E; zinc salt is dissolved in organic solvent to prepare reaction solution F; reaction solution F is added dropwise to reaction solution E at a certain temperature T6, and then the reaction is carried out at a certain temperature T7 to obtain transition intermediate X; then ammonium salt and aldehyde are added, and the reaction is carried out at a certain temperature T8 to obtain transition intermediate Y; finally, at a certain temperature T9, the pH of the reaction solution is adjusted to obtain the target product compound VI, which is polypyrene zinc; The compound VI is ; The zinc salt is zinc acetate dihydrate; The ammonium salt is ammonium acetate and ammonium chloride; The aldehyde is at least one of trioxymethylene and paraoxymethylene; The temperature T6 is 10-20℃; the temperature T7 is 20-30℃; the temperature T8 is 60-70℃; and the temperature T9 is 5-15℃.

2. The method of claim 1, wherein the poly-PRZ is prepared by the process comprising the steps of: The base used in step S1 is at least one of triethylamine, pyridine, and N,N-diisopropylethylamine; The organic solvent used in step S1 is at least one of acetonitrile, tetrahydrofuran, and dichloromethane; The reaction temperature in step S1 is 0-5℃.

3. The method of claim 1, wherein the poly-PRZ is prepared by the steps of: In step S2, the organic solvent is at least one of tetrahydrofuran and 1,4-dioxane.

4. The method for preparing polypyridine zinc according to claim 1, characterized in that, In step S2, the molar ratio of compound IV to the ligand is 1:(0.018-0.028). The molar ratio of compound IV to the metal salt is 1:(0.012-0.016). The molar ratio of compound IV to the reducing agent is 1:(2.0-2.2). The molar ratio of compound IV to compound III is 1:(1.1-1.2). The molar ratio of compound IV to chlorosilane is 1:(1.15-1.26). The molar ratio of ligand to metal salt is (1.5-1.8):1.

0.

5. The method for preparing polypyridine zinc according to claim 1, characterized in that, In step S3, the organic solvent is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

6. The method for preparing polypyridine zinc according to claim 1, characterized in that, In step S3, the molar ratio of compound V to zinc acetate dihydrate is 1:(1.1-1.2). The molar ratio of compound V to ammonium acetate is 1:(0.2-0.3), the molar ratio of compound V to ammonium chloride is 1:(0.8-0.9), and the molar ratio of ammonium acetate to ammonium chloride is 1.0:(2.5-3.2).

7. The method for preparing polypyridine zinc according to claim 1, characterized in that, In step S3, the specific operation for adjusting the pH of the reaction solution is as follows: the reaction system is adjusted to pH < 2.5 using hydrochloric acid aqueous solution; then the pH of the reaction system is adjusted to 6.4-6.6 using sodium hydroxide aqueous solution.

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