Process for the preparation of gliclazide

Abstract

The application provides a preparation process of glipizide, which comprises the following steps: 1) preparing N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride; 2) in the presence of a cerium-based activated carbon catalyst, N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride and hydrazine hydrate are subjected to a reduction reaction in a first organic solvent; after the reaction is completed, filtration is performed, the filtrate is diluted with water, and then extraction, acidification and pH adjustment to 1.5-2.5, low-temperature crystallization, filtration and drying are sequentially performed to obtain N-amino-3-azabicyclo[3.3.0]octane hydrochloride; the cerium-based activated carbon catalyst is prepared by loading a cerium salt on an activated carbon carrier through a precipitation method; and 3) N-amino-3-azabicyclo[3.3.0]octane hydrochloride and p-toluenesulfonylurea are subjected to a heating reflux reaction; after the reaction is completed, post-treatment is performed to obtain glipizide. The whole process does not emit heavy metals, the catalyst can be used repeatedly, and the treatment cost of three wastes is greatly reduced, so that the application provides a green industrialized preparation process chain of glipizide.

Description

Technical Field

[0001] This invention relates to the field of active pharmaceutical ingredients (APIs), specifically to a process for preparing gliclazide. Background Technology

[0002] Gliclazide, also known by trade names such as Glipizide and Eritrexate, is a second-generation oral sulfonylurea hypoglycemic agent developed by the French company SERVIER in 1972. Its chemical name is 1-(3-azabicyclo[3.3.0]octyl)-3-p-toluenesulfonylurea. Gliclazide exhibits excellent extrapancreatic effects, enhancing insulin receptor sensitivity and promoting insulin binding to receptors in target organs, effectively regulating blood glucose levels. These pharmacological properties have secured its important clinical position in the treatment of type 2 diabetes, resulting in consistently stable market demand.

[0003] The industrial production of gliclazide mainly adopts a three-step synthetic route: starting with 3-azabicyclo[3.3.0]octane, it first undergoes a nitrosylation reaction to generate N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride; then, it is converted to N-amino-3-azabicyclo[3.3.0]octane hydrochloride through a reduction reaction; finally, it is condensed with p-toluenesulfonylurea to obtain the target product gliclazide. Among these steps, the second step, the nitrosylation reduction reaction, is the key step in the process.

[0004] In current industrial production, the aforementioned nitrosamine reduction step commonly uses a zinc powder / hydrochloric acid system as the reducing agent. However, this method has several technical drawbacks: firstly, the zinc powder reduction process generates a large amount of zinc-containing waste residue and wastewater, causing serious heavy metal environmental pollution, and zinc ions easily remain in the product, increasing the difficulty of purification; secondly, zinc powder is a flammable solid, posing a dust explosion risk, and hydrochloric acid is highly corrosive to equipment, resulting in poor operational safety. More importantly, N-nitrosamines are impurities with clear genotoxicity. When using the zinc powder reduction method, the residual nitrosamine impurities in the reduction product are difficult to remove effectively and cannot be stably controlled at extremely low levels, posing a potential risk to drug safety.

[0005] To address the aforementioned issues, existing technologies have made numerous attempts at improvement. For example, the literature "Research on the Synthesis of Gliclazide" (Chemical and Biological Engineering, 2014, 31(7): 47-49) and "Research on New Synthetic Technologies of Gliclazide" (Master's Thesis, Jinan University, 2013) have conducted optimization studies on the synthesis process; patent literatures JP05065270, JP06041073, CN101235011, CN201710093710.7, CN102382034A, CN116283719A, and CN202510694081.8 respectively involve optimization of reaction conditions, catalyst screening, and improvement of post-treatment methods. However, none of the above-mentioned existing technologies have been able to simultaneously resolve the core contradiction between controlling genotoxic impurities and heavy metal pollution, and lacks an industrially feasible solution that can achieve high yield, high purity, low impurity residue, and environmental friendliness. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention discloses a glibenclamide preparation process that can achieve extremely low levels of residual genotoxic impurities from nitrosamines, avoid the use of heavy metal reducing agents such as zinc powder, and maintain mild reaction conditions and high yield.

[0007] To achieve the above technical objectives, this invention proposes a process for preparing gliclazide, comprising the following steps: Step 1: Dissolve 3-azabicyclo[3.3.0]octane hydrochloride in an acidic aqueous solution, add sodium nitrite to carry out a nitrosation reaction; after the reaction is completed, separate the contents to obtain N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride; Step 2: In the presence of a cerium-based activated carbon catalyst, the N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride and hydrazine hydrate are subjected to a reduction reaction in a first organic solvent; after the reaction is completed, the catalyst is recovered by filtration and reused, the filtrate is diluted with water and then extracted, acidified to adjust the pH to 1.5~2.5, crystallized at low temperature, filtered and dried to obtain N-amino-3-azabicyclo[3.3.0]octane hydrochloride; wherein, the cerium-based activated carbon catalyst is prepared by precipitation of cerium salt using activated carbon as a support; Step 3: The N-amino-3-azabicyclo[3.3.0]octane hydrochloride is heated and refluxed with p-toluenesulfonylurea in a second organic solvent; after the reaction is completed, the second solvent is removed, and the residue is subjected to water precipitation, filtration, ethanol solution slurrying, recrystallization and drying to obtain the gliclazide.

[0008] In the above technical solution, in the reduction step of the key intermediate N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride, a synergistic system of cerium-based activated carbon catalyst catalyzing the reduction of hydrazine hydrate is innovatively adopted, combined with a specific acid precipitation crystallization purification method, achieving a significant improvement in technical efficiency. Specifically: First, based on numerous experiments, the research team of this invention unexpectedly discovered that using cerium hydroxide for the selective reduction of nitrosamines has an excellent synergistic effect with hydrazine hydrate in ethanol solvent. Not only are the reaction conditions mild and highly selective, but the catalyst can also be recovered through simple filtration and recycled after washing with water, thus avoiding the problems of heavy metal pollution and one-time catalyst consumption that exist in the zinc powder reduction method.

[0009] Furthermore, in the post-treatment of the reduction reaction, the research team optimized and determined the specific pH window for acid precipitation crystallization through numerous experiments. Combined with the highly efficient cerium-based activated carbon catalyst, the above technical solution allows for low-temperature crystallization of the extracted material after the reduction reaction within a pH range of 1.5–2.5. This effectively controls the residual N-nitroso genotoxic impurities in the reduction product to an extremely low level below 0.05 ppm. Further integration with the ethanol solution slurrying and recrystallization in step 3 further ensures the quality of the final product, Glucotrol.

[0010] As is well known in the field, nitrosamines possess clear genotoxicity and are critical impurities that must be strictly controlled in the synthesis of gliclazide. Existing technologies, even with multiple recrystallizations, struggle to reduce them to this level. This invention, through the synergistic effect of a catalyst system and specific acid precipitation crystallization parameters, achieves a high yield, high purity, and low impurity residue with only simple post-processing operations, resulting in a gliclazide product that meets the ICH M7 guidelines for genotoxic impurity regulation.

[0011] In a further example of the present invention, the specific operation and parameter control of step 1 were explored and optimized.

[0012] Optionally, step (1) includes: step 1.1: dissolving 3-azabicyclo[3.3.0]octane hydrochloride in water, and then adjusting the pH value to 1~2; step 1.2: adding a saturated aqueous solution of sodium nitrite dropwise to carry out the nitrosation reaction; step 1.3: after the addition is completed, continue to keep warm until the reaction is complete, then let it stand to separate the layers, and separate the oil phase N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride.

[0013] The embodiments of the present invention confirm that, through a simple static layering operation, the boiling range of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride obtained in step 1 is 91~94℃, and it can be directly used in the next reaction without purification.

[0014] Further optionally, the molar ratio of the 3-azabicyclo[3.3.0]octane hydrochloride to the sodium nitrite is 1:(1.5~3.0), which can promote the complete nitrosation reaction and compensate for the decomposition loss of sodium nitrite under acidic conditions, while avoiding the occurrence of excessive nitrosation side reactions. This achieves a high yield of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride and provides high-quality raw materials for subsequent reduction steps. In an optional example of the present invention, the molar ratio of the 3-azabicyclo[3.3.0]octane hydrochloride to the sodium nitrite is 1:(1.8~2.5).

[0015] Further optionally, in step 1.1, the mass concentration of the 3-azabicyclo[3.3.0]octane hydrochloride solution is 50%~70%, which helps the hydrochloride to fully dissolve or disperse in the acidic medium; the nitrosation reaction is carried out at a relatively low temperature, and controlling the concentration of the 3-azabicyclo[3.3.0]octane hydrochloride solution within a suitable range allows the sodium nitrite to fully contact the amino group after its addition, improving the reaction efficiency and avoiding the generation of byproducts due to excessive concentration.

[0016] Further optionally, in step 1.2, the temperature of the nitrosation reaction is 0~30℃.

[0017] Alternatively, the dropping rate of the sodium nitrite saturated aqueous solution is adjusted to control the temperature of the reaction solution.

[0018] Alternatively, the temperature for heat preservation in step 1.3 is 65~70℃, and the heat preservation time is 0.2~1.5h.

[0019] In a further example of the present invention, the specific operation and parameter control of step 2 were explored and optimized.

[0020] Optionally, the molar ratio of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride to hydrazine hydrate is 1:(1.2~2.0). Appropriate molar ratio control can improve the reaction rate and selectivity, while controlling the excess hydrazine hydrate ensures complete reduction of the nitroso group to the amino group, avoiding genotoxic residues. Subsequent extraction operations ensure that the excess hydrazine hydrate remains in the aqueous phase. Controlling the amount of reducing agent within a suitable range can reduce the post-processing burden and cost increase caused by excess reducing agent. In an optional example of the present invention, the molar ratio of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride to hydrazine hydrate is 1:(1.3~1.6).

[0021] Optionally, the acidification adjusts the pH to 1.5-2.0. Within this pH window, the target product N-amino-3-azabicyclo[3.3.0]octane can be protonated to form hydrochloride, resulting in a sharp decrease in solubility and preferential low-temperature crystallization, yielding high-purity N-amino-3-azabicyclo[3.3.0]octane hydrochloride in high yield. Meanwhile, neutral nitrosyl impurities have a weak protonation tendency and tend to remain in the mother liquor phase. Further, optionally, the pH of the system is adjusted by adding hydrochloric acid (e.g., 3M hydrochloric acid).

[0022] Optionally, step (2) includes dissolving the N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride in the first organic solvent, followed by the dropwise addition of an aqueous solution of hydrazine hydrate. Further optionally, the mass concentration of the aqueous solution of hydrazine hydrate is 60%~80%. Further optionally, the dropping rate of the hydrazine hydrate solution is primarily controlled to ensure the reaction solution temperature does not exceed 30°C.

[0023] Optionally, the reduction reaction is carried out at a temperature of 60-70°C to provide sufficient activation energy, which can significantly accelerate the reaction rate and avoid the generation of byproducts due to excessively high temperature.

[0024] Optionally, the amount of catalyst used is 1% to 5% of the mass of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride. A suitable amount of catalyst can provide sufficient active sites and improve reaction efficiency.

[0025] Optionally, the preparation process of the catalyst includes: S1: Mix the cerium salt solution with activated carbon particles by stirring; S2: Add 10wt%~20wt% sodium hydroxide solution to adjust the pH to 8~9; then stir the reaction for about 0.5~1.5h, filter, and dry at 55~65℃ for 1.5~2.5h to obtain the catalyst.

[0026] Optionally, the particle size of the activated carbon particles ranges from 1 to 6 mm.

[0027] Optionally, the cerium salt is selected from at least one of cerium chloride and cerium nitrate. Understandably, the cerium salt is a water-soluble salt to facilitate subsequent precipitation operations.

[0028] Optionally, the loading of the active component, based on metal elements, is 5-10%.

[0029] Optionally, the first organic solvent is selected from at least one of ethanol, aqueous ethanol solution, methanol, and acetonitrile.

[0030] Optionally, the mass ratio of the first organic solvent to the N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride is (0.5~2.0):1. In an optional example of the present invention, the mass ratio of the first organic solvent to the N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride is (0.6~1.5):1.

[0031] It should be noted that in step 2 of this invention, diluting the filtrate with water can break the phase equilibrium of the solvent system and promote product transfer. Hydrazine hydrate is easily soluble in water, so the interference of hydrazine hydrate can be reduced and the extraction selectivity can be improved by adding water. Optionally, pure water can be added at a volume ratio of 1:(4~6) to improve the extraction selectivity and extraction efficiency.

[0032] Optionally, the extractant used in step (2) is selected from at least one of ethyl acetate and dichloromethane.

[0033] Optionally, the low-temperature crystallization temperature is 0~5℃. By crystallizing at this temperature for 0.5~2h, a light yellow crystalline powder of N-amino-3-azabicyclo[3.3.0]octane hydrochloride can be obtained in high yield.

[0034] It should be noted that step 2 also includes, after the extraction operation, using an extractant to extract and wash the aqueous phase, and combining the resulting extract phase with the extractant phase obtained in the aforementioned operation, in order to fully recover the target product.

[0035] It should be noted that step 2 also includes a water washing operation on the extractant phase obtained after the extraction operation to remove impurities.

[0036] In a further example of the present invention, the specific operation and parameter control of step 3 were explored and optimized.

[0037] Optionally, the molar ratio of the N-amino-3-azabicyclo[3.3.0]octane hydrochloride to the p-toluenesulfonylurea is (1.05~1.3):1, thereby promoting the complete conversion of p-toluenesulfonylurea and inhibiting its own condensation side reaction, achieving efficient condensation and high-purity preparation of gliclazide. In an optional example of the present invention, the molar ratio of the N-amino-3-azabicyclo[3.3.0]octane hydrochloride to the p-toluenesulfonylurea is (1.08~1.2):1.

[0038] Optionally, the reflux reaction temperature is 90~110℃.

[0039] Optionally, the second organic solvent is selected from at least one of toluene, DMF, and xylene.

[0040] Optionally, the mass ratio of the second organic solvent to the N-amino-3-azabicyclo[3.3.0]octane hydrochloride is (4~8):1. In an optional example of the present invention, the mass ratio of the second organic solvent to the N-amino-3-azabicyclo[3.3.0]octane hydrochloride is (5~7):1.

[0041] It should be noted that the present invention does not limit the specific operation for removing the second solvent from the reaction material. For example, it can be removed by distillation, rotary evaporation or other methods. Those skilled in the art can choose according to their needs.

[0042] Optionally, the concentration of the ethanol solution used for pulping is 20wt% to 30wt% (volume concentration). Optionally, the solvent used for recrystallization is selected from at least one of ethyl acetate and acetonitrile. Through post-treatment operations including pulping with an ethanol solution and recrystallization, the raw materials, impurities, and solvents contained in the target product gliclazide can be further removed, thereby improving purity.

[0043] Optionally, the volume of the ethanol solution used for pulping is 2 to 4 times the weight of the solid wet product to ensure sufficient solid-liquid contact while avoiding excessive dilution. Optionally, the pulping operation temperature is 20 to 40°C, and the time is 0.5 to 3 hours. Optionally, the water precipitation process of the residue includes adding water to the residue, stirring, and precipitating the water, followed by filtration to obtain a solid wet product. Further optionally, the amount of purified water used is 4 to 6 times the weight of the residue; the water precipitation process is performed at room temperature to 30°C for 0.5 to 2 hours.

[0044] It should be noted that in actual operation, the completeness of the reaction can be monitored by methods such as gas chromatography, high performance liquid chromatography, or ultraviolet-visible spectroscopy.

[0045] Compared with existing technologies, the beneficial effects of this invention are as follows: In the reduction step of the key intermediate N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride, this invention innovatively adopts a synergistic system of cerium-based activated carbon catalyst catalysis and hydrazine hydrate reduction. This not only provides mild reaction conditions and high selectivity, but also allows for simple filtration and recycling after water washing, avoiding the heavy metal pollution and one-time catalyst consumption problems of traditional zinc powder reduction methods. Combined with acid precipitation and crystallization of the extracted material in the pH range of 1.5~2.5 during the post-reduction reaction treatment, the residual N-nitroso genotoxic impurities in the reduction product can be stably controlled at an extremely low level of less than 0.05 ppm. Furthermore, combined with the subsequent synergistic purification of ethanol solution slurrying and recrystallization, the final purity of gliclazide product is >99.5%, and the content of key genotoxic impurities meets the most stringent regulatory requirements of ICH M7 guidelines.

[0046] The present invention has no heavy metal emissions, the catalyst can be reused multiple times, and the cost of waste treatment is greatly reduced. It has the advantages of high yield, high purity, safety, environmental friendliness and low production cost, and forms a complete green industrial preparation process chain for gliclazide. Attached Figure Description

[0047] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The test report of glibenclamide prepared according to Embodiment 1 of the present invention is shown.

[0048] Figure 2 The test report for glibenclamide prepared according to Embodiment 2 of the present invention is shown.

[0049] Figure 3 The test report for glibenclamide prepared according to Embodiment 3 of the present invention is shown. Detailed Implementation

[0050] To facilitate understanding of the present invention, a more comprehensive description will be provided below, along with preferred embodiments. However, it should be understood that these embodiments are merely for more detailed explanation and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of protection of the invention.

[0051] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0052] Furthermore, it should be noted that although the various steps of the preparation method of the present invention are described in a specific order in the description of the present invention, these orders are not restrictive. Without departing from the basic principles of the present invention, those skilled in the art can perform the steps in different orders.

[0053] Furthermore, the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined with "first," "second," etc., may explicitly or implicitly include one or more of that feature. In the description of this invention, unless otherwise stated, "multiple" or "at least one" means two or more.

[0054] All numerical designations, such as pH, temperature, length, flow rate, and range, are approximate values. It should be understood that, while not always explicitly stated, all numerical designations are preceded by the term "approximately." It should also be understood that, while not always explicitly stated, the reagents described herein are merely examples, and their equivalents are known in the art.

[0055] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0056] Example 1

[0057] A process for preparing gliclazide, specifically: Step 1: Add 2.0L of purified water and 3.50kg (23.70mol) of 3-azabicyclo[3.3.0]octane hydrochloride to a 20L reactor. Adjust the pH of the solution to 1.0-1.5 by adding 3M hydrochloric acid dropwise. Add 3.60kg (52.15mol) of sodium nitrite dropwise to prepare a saturated aqueous solution, completing the addition over approximately 2 hours, while maintaining the pH of the reaction solution between 1.0 and 1.5. After the addition is complete, continue stirring and maintaining the temperature for 0.5 hours. Raise the temperature to 65-70℃ and monitor the reaction for completeness using gas chromatography. Allow the mixture to stand and separate into layers. The upper layer separates into 4.23kg of a pale yellowish-brown oily liquid of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride, with a product yield of 101% (may contain water). Product quality testing: Boiling range 91-94℃, no purification required, can be used directly in the next reaction step.

[0058] Step 2: Add 4.0 kg (22.64 mol) of the product from the previous step, 80 g of cerium-based activated carbon catalyst (cerium loading of 8%), and 3 L of ethanol to a 20 L reactor; stir, control the temperature below 20 °C, and add 2.13 kg (33.96 mol) of 80% hydrazine hydrate dropwise. After the addition is complete, control the temperature at 60-70 °C and monitor the reaction until complete; after stirring and cooling, filter, and the filtered solid (catalyst) can be reused after washing with water; add 9 L of purified water and 6 L of ethyl acetate to the filtrate; separate the liquid and extract the aqueous phase with 2 L of ethyl acetate, and combine the ethyl acetate phases; then wash the ethyl acetate phase with 4 L of water, adjust the pH of the ethyl acetate phase with concentrated hydrochloric acid solution to 1.5-2.0, cool at 0-5 °C for 1 h to crystallize, centrifuge and filter, dry the solid at 55-60 °C, and weigh to obtain 3.49 g of ethanol. kg of light yellow crystalline powder (N-amino-3-azabicyclo[3.3.0]octane hydrochloride), product yield 95%, nitrosamine residue less than 0.05 ppm.

[0059] Step 3: Add 3.0 kg (18.44 mol) N-amino-3-azabicyclo[3.3.0]octane hydrochloride, 3.6 kg (16.77 mol) p-toluenesulfonylurea, and 18 L of toluene to a 50 L reactor. Heat to 95-100 °C under reflux. Monitor the reaction for completeness using thin-layer chromatography or HPLC. Remove the solvent toluene by vacuum distillation. Add 24 L of purified water to the residue, stir for 1 h, and filter. Add 12 L of 25% ethanol to the solid wet product, stir and slurry to thoroughly remove impurity I. Re-solidify the solid wet product with 6 L of ethyl acetate, and vacuum dry at 60-65 °C for 6 hours to obtain 4.75 kg of white crystalline powder with a yield of 87.5%. Product quality: HPLC purity 99.86%, impurity I (1-(3-azabicyclo[3.3.0]octyl)-3-o-toluenesulfonylurea) not detected, other maximum single impurities 0.04%, and solvent residue meets requirements.

[0060] Example 2

[0061] A process for preparing gliclazide, specifically: Step 1: Add 3.5L of purified water and 3.50kg (23.70mol) of 3-azabicyclo[3.3.0]octane hydrochloride to a 20L reactor. Adjust the pH of the solution to 1.5-2.0 by adding 3M hydrochloric acid dropwise. Add 2.95kg of sodium nitrite (42.66mol) dropwise to prepare a saturated aqueous solution, completing the addition in about 2 hours, while maintaining the pH of the reaction solution between 1.5 and 2.0. After the addition is complete, continue stirring and maintaining the temperature for 0.8 hours. Raise the temperature to 65-70℃ and monitor the reaction for completeness using gas chromatography. Allow the mixture to stand and separate into layers. The upper layer separates into 4.11kg of a pale yellowish-brown oily liquid of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride, with a product yield of 98% (possibly containing water). Product quality testing: Boiling range 91-94℃, no purification required, can be used directly in the next reaction.

[0062] Step 2: Add 4.0 kg (22.64 mol) of the product from the previous step, 200 g of cerium-based activated carbon catalyst (cerium loading of 5%), and 6 L of ethanol to a 20 L reactor; stir, control the temperature below 20 °C, and add 1.85 kg (29.43 mol) of 80% hydrazine hydrate dropwise. After the addition is complete, control the temperature at 60-70 °C and monitor the reaction until complete; after stirring and cooling, filter, and the filtered solid (catalyst) can be reused after washing with water; add 9 L of purified water and 6 L of dichloromethane to the filtrate; separate the liquid and extract the aqueous phase with 2 L of dichloromethane, and combine the dichloromethane phases; then wash the dichloromethane phase with 4 L of water, adjust the pH of the dichloromethane phase with concentrated hydrochloric acid solution to 2.0-2.5, cool at 0-5 °C for 1 h to crystallize, centrifuge and filter, dry the solid at 55-60 °C, and weigh to obtain 3.41 g of ethanol. kg of light yellow crystalline powder (N-amino-3-azabicyclo[3.3.0]octane hydrochloride), product yield 93%, nitrosamine residue less than 0.05 ppm.

[0063] Step 3: Add 3.27 kg (20.12 mol) N-amino-3-azabicyclo[3.3.0]octane hydrochloride, 3.6 kg (16.77 mol) p-toluenesulfonylurea, and 16 L of xylene to a 50 L reactor. Heat to 105-110 °C under reflux. Monitor the reaction for completeness using thin-layer chromatography or HPLC. Remove the xylene solvent by vacuum distillation. Add 24 L of purified water to the residue, stir for 1 h, and filter. Add 12 L of 25% ethanol to the solid wet product, stir and slurry to thoroughly remove impurity I. Re-solidify the solid wet product with 6 L of ethyl acetate, and vacuum dry at 60-65 °C for 6 hours to obtain 4.83 kg of white crystalline powder with a yield of 89%. Product quality: HPLC purity 99.84%, impurity I (1-(3-azabicyclo[3.3.0]octyl)-3-o-toluenesulfonylurea) not detected, other maximum single impurities 0.05%, solvent residue and other quality meet the pharmacopoeia requirements.

[0064] Example 3

[0065] A process for preparing gliclazide, specifically: Step 1: Add 2.5L of purified water and 3.50kg (23.70mol) of 3-azabicyclo[3.3.0]octane hydrochloride to a 20L reactor. Adjust the pH of the solution to 1.0-1.5 by adding 3M hydrochloric acid dropwise. Add 3.27kg (47.4mol) of sodium nitrite dropwise to prepare a saturated aqueous solution, completing the addition over approximately 2 hours, while maintaining the pH of the reaction solution between 1.0 and 1.5. After the addition is complete, continue stirring and maintaining the temperature for 0.5 hours. Raise the temperature to 65-70℃ and monitor the reaction for completeness using gas chromatography. Allow the mixture to stand and separate into layers. The upper layer separates into 4.15kg of a pale yellowish-brown oily liquid of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride, with a product yield of 99% (possibly containing water). Product quality testing: Boiling range 92-94℃, no purification required, can be used directly in the next reaction step.

[0066] Step 2: Add 4.0 kg (22.64 mol) of the product from the previous step, 120 g of cerium-based activated carbon catalyst (cerium loading of 7%), and 5 L of ethanol to a 20 L reactor; stir, control the temperature below 20 °C, and add 3.4 kg (40.75 mol) of 60% hydrazine hydrate dropwise. After the addition is complete, control the temperature at 60-70 °C and monitor the reaction until complete; after stirring and cooling, filter, and the filtered solid (catalyst) can be reused after washing with water; add 9 L of purified water and 6 L of ethyl acetate to the filtrate; separate the liquid and extract the aqueous phase with 2 L of ethyl acetate, and combine the ethyl acetate phases; then wash the ethyl acetate phase with 4 L of water, adjust the pH of the ethyl acetate phase with concentrated hydrochloric acid solution to 1.5-2.0, cool at 0-5 °C for 1 h to crystallize, centrifuge and filter, dry the solid at 55-60 °C, and weigh to obtain 3.53 g / mL. kg of light yellow crystalline powder (N-amino-3-azabicyclo[3.3.0]octane hydrochloride), product yield 96%, nitrosamine residue less than 0.05 ppm.

[0067] Step 3: Add 2.95 kg (18.11 mol) N-amino-3-azabicyclo[3.3.0]octane hydrochloride, 3.6 kg (16.77 mol) p-toluenesulfonylurea, and 21 L of toluene to a 50 L reactor. Heat to reflux and monitor the reaction for completeness using thin-layer chromatography or HPLC. Remove the solvent toluene by vacuum distillation. Add 24 L of purified water to the residue, stir for 1 h, and filter. Add 12 L of 20% ethanol to the solid wet product and stir to thoroughly remove impurity I. Re-crystallize the solid wet product with 6 L of acetonitrile and vacuum dry at 60-65 °C for 6 hours to obtain 4.69 kg of white crystalline powder with a yield of 86.5%. Product quality: HPLC purity 99.85%, impurity I (1-(3-azabicyclo[3.3.0]octyl)-3-o-toluenesulfonylurea) not detected, other maximum single impurities 0.05%, solvent residue and other physicochemical items meet the pharmacopoeia requirements.

[0068] It should be noted that the above description is a further detailed explanation of the present invention in conjunction with specific embodiments, and it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, several simple improvements can be made without departing from the concept of the present invention, and all such improvements should be considered to fall within the scope of protection of the present invention.

Claims

1. A process for preparing gliclazide, characterized in that, Includes the following steps: Step 1: Dissolve 3-azabicyclo[3.3.0]octane hydrochloride in an acidic aqueous solution, add sodium nitrite to carry out a nitrosation reaction; after the reaction is completed, separate the contents to obtain N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride; Step 2: In the presence of a cerium-based activated carbon catalyst, the N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride and hydrazine hydrate are subjected to a reduction reaction in a first organic solvent; after the reaction is completed, the catalyst is recovered by filtration and reused, the filtrate is diluted with water and then extracted, acidified to adjust the pH to 1.5~2.5, crystallized at low temperature, filtered and dried to obtain N-amino-3-azabicyclo[3.3.0]octane hydrochloride; wherein, the cerium-based activated carbon catalyst is prepared by precipitation of cerium salt using activated carbon as a support; Step 3: The N-amino-3-azabicyclo[3.3.0]octane hydrochloride is heated and refluxed with p-toluenesulfonylurea in a second organic solvent; after the reaction is completed, the second solvent is removed, and the residue is subjected to water precipitation, filtration, ethanol solution slurrying, recrystallization and drying to obtain the gliclazide.

2. The glibenclamide preparation process according to claim 1, characterized in that, Step (1) includes: Step 1.1: Dissolve 3-azabicyclo[3.3.0]octane hydrochloride in water, and then adjust the pH to 1-2; Step 1.2: Add saturated aqueous solution of sodium nitrite dropwise to carry out the nitrosation reaction; Step 1.3: After the addition is complete, continue to keep warm until the reaction is complete, then let it stand to separate the layers, and separate the oil phase N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride.

3. The glibenclamide preparation process according to claim 2, characterized in that, The molar ratio of the 3-azabicyclo[3.3.0]octane hydrochloride to the sodium nitrite is 1:(1.5~3.0), preferably 1:(1.8~2.5). And / or, in step 1.1, the mass concentration of the 3-azabicyclo[3.3.0]octane hydrochloride solution is 50%~70%; And / or, in step 1.2, the temperature of the nitrosation reaction is 0~30℃; And / or, the temperature for heat preservation in step 1.3 is 65~70℃, and the heat preservation time is 0.2~1.5h.

4. The glibenclamide preparation process according to claim 1, characterized in that, The molar ratio of N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride to hydrazine hydrate is 1:(1.2~2.0), preferably 1:(1.3~1.6); And / or, the acidification adjusts the pH to 1.5-2.0; And / or, the temperature of the reduction reaction is 60~70℃.

5. The glibenclamide preparation process according to claim 1, characterized in that, Based on metal elements, the amount of the cerium-based activated carbon catalyst is 1% to 5% of the mass of the N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride; And / or, the cerium salt is selected from at least one of cerium chloride and cerium nitrate; And / or, based on metal elements, the loading of the active component is 5-10%.

6. The glibenclamide preparation process according to claim 1, characterized in that, The first organic solvent is selected from at least one of ethanol, aqueous ethanol solution, methanol, and acetonitrile; And / or, the mass ratio of the first organic solvent to the N-nitroso-3-azabicyclo[3.3.0]octane hydrochloride is (0.5~2):1, preferably (0.6~1.5):

1.

7. The glibenclamide preparation process according to claim 1, characterized in that, The extractant used in step (2) is selected from at least one of ethyl acetate and dichloromethane.

8. The glibenclamide preparation process according to claim 1, characterized in that, The molar ratio of the N-amino-3-azabicyclo[3.3.0]octane hydrochloride to the p-toluenesulfonylurea is (1.05~1.3):1, preferably (1.08~1.2):1; And / or, the reflux reaction temperature is 90~110°C.

9. The glibenclamide preparation process according to claim 1, characterized in that, The second organic solvent is selected from at least one of toluene, DMF, and xylene; And / or, the mass ratio of the second organic solvent to the N-amino-3-azabicyclo[3.3.0]octane hydrochloride is (4~8):1, preferably (5~7):

1.

10. The glibenclamide preparation process according to claim 1, characterized in that, The concentration of the ethanol solution used for pulping is 20wt%~30wt%; And / or, the solvent used for recrystallization is selected from at least one of ethyl acetate and acetonitrile.

Images