New process for producing alfacalcidol bulk drug

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and discloses a novel process for producing an alfacalcidol raw material medicine, which comprises the following steps of: introducing a Lewis acid catalyst in a key addition reaction, obviously shortening the reaction time and inhibiting side reaction; a quenching mode of dilution dropwise adding and real-time pH and temperature monitoring is adopted to replace one-time adding of a quenching agent, so that product decomposition or polymerization caused by too high local concentration is avoided; an acetone-ethanol cosolvent system is combined with a programmed gradient cooling crystallization process, so that the freezing point of the solvent is reduced, and crystals with uniform particle size and good fluidity are obtained; and a microwave-vacuum combined drying technology is adopted, so that the drying efficiency is greatly improved, and the moisture absorption stability of the product is improved. The method has the advantages of high overall efficiency, stable product quality, significantly improved product purity and yield, and suitableness for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, specifically to a new process for producing alfacalcidol active pharmaceutical ingredient. Background Technology

[0002] Alfacalcidol is an analogue of calcitriol (1,25-dihydroxyvitamin D3), serving as a prodrug that is converted to the biologically active calcitriol via hydroxylation in the liver. Clinically, it is primarily used to treat osteoporosis, renal osteodystrophy, and hypoparathyroidism. Its market demand continues to grow, making the development of efficient, stable, and environmentally friendly industrial production processes crucial. Current synthetic processes for alfacalcidol typically involve a Diels-Alder addition reaction of the key intermediate GHC07 with maleic anhydride to construct its core structure, as shown in the reaction formula below. Figure 1 As shown. Under conventional conditions (without a catalyst or using a conventional catalyst), this reaction suffers from problems such as long reaction time (usually 12-18 hours), low efficiency, and easy generation of byproducts (such as 9-acetylanthracene residue), which increases the burden and cost of subsequent purification.

[0003] Furthermore, existing processes typically involve a one-time addition of high-concentration triethylamine in the quenching step, which can easily lead to a sharp increase in local pH and temperature, triggering side reactions such as decomposition or polymerization of the target product, thus affecting product quality and yield. In the crystallization and purification step, a single solvent (such as pure acetone) and simple low-temperature static crystallization are often used, resulting in problems such as high solvent consumption, uneven crystallization rate, wide crystal particle size distribution, and easy agglomeration of the filter cake, leading to filtration difficulties. The drying step usually uses a traditional vacuum drying oven, which has a long drying time (approximately 3 hours), high energy consumption, and the dried product is prone to moisture absorption, affecting stability. Summary of the Invention

[0004] The purpose of this invention is to provide an optimized method for the production reaction system of alfacalcidol active pharmaceutical ingredient, aiming to shorten the reaction time, improve the reaction selectivity, optimize the quenching and crystallization process, and improve the drying efficiency, ultimately achieving a comprehensive improvement in product purity, yield, and stability.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A new process for producing alfacalcidol active pharmaceutical ingredient includes the following steps:

[0007] (1) Catalytic addition reaction: In the reaction system of intermediate GHC07 and maleic anhydride, a Lewis acid catalyst is added and the reaction is carried out for 4 to 6 hours under an inert atmosphere.

[0008] (2) Quenching and post-treatment: The quenching agent is prepared into a diluted solution and added dropwise to the reaction solution in step (1) at a uniform rate. During the dropwise addition, the pH value of the reaction system is monitored and maintained at 8-9, and the temperature of the reaction solution is ≤25℃. After stirring, the solution is concentrated to obtain an oily substance.

[0009] (3) Column chromatography purification: The oily substance obtained by concentration in step (2) is separated by silica gel column chromatography, the eluent containing the target intermediate GHC08 is collected, and the solid is concentrated.

[0010] (4) Gradient crystallization: The solid obtained by concentration in step (3) is dissolved in acetone-ethanol co-solvent, heated to dissolve, and then crystallized by programmed gradient cooling.

[0011] (5) Filtration and drying: The crystallization liquid from step (4) was filtered, the filter cake was rinsed with cold solvent, and then dried in a microwave-vacuum combined drying equipment to obtain crude alfacalcidol GHC08.

[0012] Preferably, in step (1), the Lewis acid catalyst is selected from at least one of ZnCl2, BF3·Et2O, and AlCl3.

[0013] More preferably, the amount of Lewis acid catalyst added is 0.5 to 2% of the weight of intermediate GHC07.

[0014] Preferably, in step (2), the quenching agent is triethylamine, and the diluent is a methanol solution of triethylamine with a concentration of 15-25% (w / w).

[0015] Preferably, in step (4), the volume ratio of acetone to ethanol in the acetone-ethanol co-solvent is 2:1 to 4:1.

[0016] More preferably, the volume ratio of acetone to ethanol is 3:1.

[0017] Preferably, in step (4), the programmed gradient cooling method includes:

[0018] First, cool down to 25-35°C at a rate of 3-7°C / hour, and hold for 1-3 hours;

[0019] Then cool down to -2 to 2°C at a rate of 1 to 3°C / hour, and keep warm for 3 to 5 hours;

[0020] Finally, cool down to -20 to -10°C at a rate of 2 to 4°C / hour and hold for 5 to 7 hours.

[0021] More preferably, in step (4), the programmed gradient cooling method includes:

[0022] First, cool down to 30°C at a rate of 5°C / hour and hold for 2 hours;

[0023] Then cool down to -0℃ at a rate of 2℃ / hour and hold for 4 hours;

[0024] Finally, the temperature was lowered to -15°C at a rate of 3°C / hour and held for 6 hours.

[0025] Preferably, in step (5), the conditions for microwave-vacuum combined drying are: drying temperature 30-40℃, vacuum degree 0.08-0.1MPa, microwave power density 1-3W / g, and drying time 40-60 minutes.

[0026] Preferably, in step (5), the cold solvent used for rinsing is acetone or an acetone-ethanol mixture pre-cooled to below -15°C.

[0027] Preferably, the method further includes further purification of the crude alfacalcidol GHC08 obtained in step (5) to obtain high-purity alfacalcidol.

[0028] The present invention adopts the above technical solution and has the following technical effects compared with the prior art:

[0029] (1) Significantly improved reaction efficiency: The use of composite catalysts shortens the key addition reaction time by more than 60%, improves equipment utilization, and increases production capacity.

[0030] (2) Improved product quality: Through catalytic inhibition and controllable quenching, the residual amount of by-products (such as 9-acetylanthracene) is reduced by about 40%, and the purity of intermediate GHC08 is increased by about 5 to 7 percentage points.

[0031] (3) More precise and stable process control: The dilution and addition combined with the quenching method of online pH / temperature monitoring makes the operation shift from experience-based to parameterized, resulting in better batch reproducibility and more stable quality.

[0032] (3) Crystallization process optimization: The combination of co-solvent system and gradient crystallization process improves crystal morphology, increases filtration speed and product flowability, and reduces the consumption of single solvent.

[0033] (4) Reduced energy consumption and enhanced product stability: Microwave-vacuum combined drying significantly shortens drying time by 75%, saving energy and reducing consumption; the moisture absorption of dried products is reduced, improving the long-term storage stability of raw materials.

[0034] (5) High overall yield: Due to the reduction of losses in each step, the overall yield of the optimized process is about 2 percentage points higher than that of the original process. Attached Figure Description

[0035] Figure 1 This is the reaction formula for the alfacalcidol raw material GHC08 of the present invention.

[0036] Figure 2 This is the HPLC chromatogram of the crude alfacalcidol raw material GHC08 obtained in Example 1 of the present invention. Detailed Implementation

[0037] This invention provides an optimized method for the production reaction system of alfacalcidol active pharmaceutical ingredient. The core technical solution involves introducing a Lewis acid-ionic liquid composite catalyst into the critical addition reaction, which significantly shortens the reaction time and suppresses side reactions. A quenching method using dilution and dropwise addition with real-time pH and temperature monitoring replaces the one-time addition of the quencher, avoiding product decomposition or polymerization caused by excessively high local concentrations. An acetone-ethanol co-solvent system combined with a programmed gradient cooling crystallization process lowers the solvent freezing point, resulting in crystals with uniform particle size and good flowability. Finally, a microwave-vacuum combined drying technology significantly improves drying efficiency and enhances the product's moisture absorption stability.

[0038] (I) In the catalytic addition reaction process, a Lewis acid-ionic liquid composite catalyst of a specific composition is added to the reaction system of intermediate GHC07 and maleic anhydride in a dichloromethane / ethyl acetate mixed solvent. This catalyst can effectively reduce the activation energy of the reaction, significantly shorten the reaction time from the traditional 12-18 hours to 4-6 hours, and significantly inhibit the formation of by-products.

[0039] It is worth noting that in the synthesis of the alfacalcidol intermediate GHC07, the preceding photochemical reaction often fails to completely convert the starting material GHC06, resulting in approximately 1-3% residual GHC06 impurity in the product GHC07. This impurity has a similar structure and polarity to the target product GHC07, making it difficult to separate effectively using conventional chromatographic or crystallization methods. Existing techniques employ a stoichiometric Diels-Alder reaction between maleic anhydride and GHC06 to generate a more polar adduct, thus achieving separation. However, this method suffers from drawbacks such as long reaction time (12-18 hours), low yield (50-70%), and high solvent consumption.

[0040] Based on considerations of catalytic activity and selectivity balance and post-treatment convenience, experiments verified that ZnCl2, BF3·Et2O, and AlCl3 were selected as Lewis acid catalysts. The chosen Lewis acids possess moderate coordination ability for the electron-deficient carbonyl group in maleic anhydride, effectively reducing its LUMO energy and accelerating the cycloaddition with GHC06 (as a diene), while avoiding overactivation or side reactions of sensitive conjugated olefins or potential hydroxyl groups in the GHC07 molecule. Furthermore, the selected ZnCl2 and BF3·Et2O can be quenched with alkaline water after the reaction to form soluble salts or easily decomposed substances, facilitating removal and meeting the stringent metal residue control requirements of pharmaceutical production. Specifically, the screening experiments for the types and amounts of Lewis acid catalysts are shown in Tables 1 and 2 below.

[0041] Table 1 Catalyst Screening Experiment

[0042]

[0043] Table 2. Experiment on optimization of ZnCl2 dosage

[0044]

[0045]

[0046] (II) In the quenching and post-treatment process. After the catalytic reaction is complete, the quencher triethylamine is pre-prepared into a 20% (w / w) methanol diluted solution (quencher dilution), and added dropwise to the reaction solution at a uniform rate under stirring. During the dropwise addition, the pH value of the reaction solution is monitored in real time using an online pH meter, and the temperature of the reaction solution is maintained at ≤25℃ using an ice bath or temperature-controlled jacket, so that the pH of the system is stabilized within a suitable range of 8-9. This method avoids local overheating and overly alkaline environments, effectively preventing the degradation of the product during the quenching process. The specific control of each key parameter in this process step is as follows:

[0047] Regarding the dropping rate, the addition of the quencher should be completed within 30–90 minutes, preferably 45–60 minutes. The corresponding dropping rate can be adjusted according to the total volume of the reaction solution, typically 0.5–2% of the total volume of the reaction solution per minute (v / v / min). This rate effectively disperses the heat of neutralization, avoiding localized overheating and sudden pH jumps.

[0048] Regarding pH monitoring and maintenance, during the dropping process, an online pH meter (preferred model: Mettler Toledo InPro 3250i series, or an industrial online pH sensor with equivalent accuracy and response speed) is used to monitor the pH value of the reaction system in real time. By adjusting the dropping rate, the pH value of the system is precisely maintained within the range of 8.0 to 9.0. This slightly alkaline environment is sufficient to effectively neutralize the acids produced in the reaction and quench Lewis acids, while avoiding product degradation under strongly alkaline conditions.

[0049] Regarding temperature control, during the dropwise addition process, the temperature of the reaction solution is controlled by a cooling bath (such as an ice-water bath) to ensure that it is always ≤25℃, preferably maintained at 20~25℃.

[0050] After the addition is complete, continue stirring at the same temperature for 15–30 minutes to ensure complete quenching. The reaction solution is then concentrated under reduced pressure using a rotary evaporator at 30–45°C and a vacuum of 0.08–0.1 MPa to obtain an oily substance for subsequent purification.

[0051] (III) In the existing preparation process of alfacalcidol intermediate GHC08, acetone is usually used as the crystallization solvent, and crystallization is achieved by simple cooling (e.g., from 60-65℃ to -10℃). This method has the following shortcomings: 1) Limited yield and purity: The solubility curve of a single solvent is limited, and its selective separation ability for impurities is limited, resulting in small room for improvement in product purity and large yield fluctuations (50-70%). 2) Poor crystal morphology: Rapid or uncontrolled cooling easily leads to small crystals, agglomeration, or oily precipitation, affecting filtration and washing efficiency, and may encapsulate impurities in the mother liquor. 3) Poor process reproducibility: It relies on empirical natural cooling, making it difficult to accurately control supersaturation and resulting in large batch-to-batch differences. Therefore, in order to overcome the technical defects of using acetone as a single crystallization solvent, a controllable, efficient and reproducible crystallization process has been developed. This process selects an acetone-ethanol co-solvent and, through scientific design of the co-solvent system and gradient cooling procedure, stably obtains high-purity, high-yield GHC08 crystals with excellent morphology.

[0052] The present invention selects an acetone-ethanol co-solvent, which has the following advantages: 1) Solubility synergy: Acetone has high solubility for GHC08, but its selectivity is generally low; ethanol has moderate solubility for GHC08, but its solubility for certain polar impurities (such as residual 9-acetylanthracene and maleic anhydride adducts) is even lower. Mixing the two creates a steeper solubility-temperature curve, which facilitates highly selective precipitation of the target product and impurities during cooling. 2) Polarity fine-tuning and impurity repulsion: Acetone (polarity index 5.1) and ethanol (polarity index 5.2) have similar polarities but different hydrogen bonding abilities. By adjusting the ratio, the hydrogen bond donor / acceptor ability and polarity of the solvent system can be precisely controlled, optimizing its interaction with GHC08 molecules while maximizing the solubility of impurities in the mother liquor. Experiments have shown that the solubility of key impurities in this co-solvent is 1.5-2 times that of acetone alone. 3) Improved crystal behavior: The addition of ethanol alters the surface tension and viscosity of the crystallization medium, guiding GHC08 molecules to stack in a more ordered manner, promoting the formation of larger, more uniform crystals, rather than amorphous solids or oily substances. 4) Safety and cost: Both are low-toxicity, readily available, and easily recyclable Class I or Class II solvents, meeting the requirements for pharmaceutical production.

[0053] The effects of different volume ratios of acetone-ethanol co-solvents on crystallization yield, purity, and crystal morphology were investigated by systematically screening them. With a fixed feed amount of 10.0 g of crude GHC08, a dissolution temperature of 60 °C, and a total solvent volume of 20 mL / g (i.e., 200 mL), the same initial cooling program (60 °C → 30 °C, rate 0.5 °C / min) was used. The results are shown in Table 3 below.

[0054] Table 3. Determination and Comparative Data of the Optimal Volume Ratio of Acetone-Ethanol Co-solvent

[0055] Acetone: Ethanol (v / v) Crystallization yield (%) HPLC purity (%) Crystal morphology description Filtering time (min) 5:1 65.2 97.8 Fine needle-like, slightly aggregated 25 4:1 71.5 98.3 Needle-shaped, relatively uniform 20 3:1 78.9 99.1 Regular flake shape, uniform particle size 15 2:1 75.4 98.9 Flake-like, slightly aggregated 18 1:1 68.7 98.5 Blocky, with a rough surface 22 Pure acetone (using existing processes) 62.0 97.5 Fine powder, severely aggregated 30+

[0056] Conclusion: A ratio of acetone to ethanol of 3:1 (v / v) achieves the best balance in yield, purity, and crystal morphology (displaying regular flaky crystals with good flowability and easy filtration and washing), making it the preferred ratio for this invention. When the ethanol ratio is too low (e.g., 5:1), it approaches the properties of pure acetone, resulting in limited improvement in performance; when the ratio is too high (e.g., 1:1), the solubility of the product decreases too rapidly at low temperatures, potentially trapping impurities, and the crystal morphology deteriorates.

[0057] The completely dissolved, clear solution was subjected to a multi-stage cooling crystallization process as follows: Stage 1 (Rapid Nucleation): The solution was cooled from its dissolution temperature of 63°C to 30°C at a rate of 5°C / h and held for two hours. This stage generates moderate supersaturation, inducing the formation of numerous uniform crystal nuclei. Stage 2 (Controlled Crystal Growth): The solution was cooled from the endpoint temperature of the previous stage to 0°C at a slow rate of 2°C / h and held for four hours. This stage maintains a low degree of supersaturation, allowing the crystal nuclei to grow orderly into large, uniform crystals and avoiding secondary nucleation. Stage 3 (Deep Crystallization and Yield Improvement): The solution was cooled from 0°C to -15°C at a rate of 3°C / h. This stage further reduces the product solubility, increases the yield, and, since stable crystals have already formed, fine crystals are less likely to form at this rate. Stage 4 (Aging Stabilization): The solution was held at -15°C for 6 hours. This allows for a more complete crystal structure, releases internal stress, and provides an opportunity for fine crystals to dissolve and recrystallize.

[0058] In summary, the key process for this gradient crystallization is as follows: the intermediate GHC08 solid obtained after column chromatography purification is dissolved in an acetone-ethanol co-solvent (preferably a volume ratio of 3:1); a programmed gradient cooling crystallization process is employed: first, the temperature is lowered at a moderate rate to approximately 30°C and held to allow for uniform crystal nuclei formation; then, the temperature is lowered at a slower rate to approximately 0°C to promote ordered crystal growth; finally, the temperature is further lowered to approximately -15°C and held to promote crystal growth. This process, combined with the co-solvent system (which lowers the freezing point of the mixed solvent), results in more uniform crystal growth, a narrower crystal particle size distribution, and a loose, free-flowing filter cake, significantly improving filtration and washing efficiency.

[0059] (iv) In the filtration and drying process, the washed wet filter cake is placed in a microwave-vacuum combined drying equipment. Under vacuum conditions, microwave energy directly acts on the water molecules inside the material, achieving rapid and uniform bulk heating, reducing the drying time from 3 hours in traditional vacuum drying to approximately 45 minutes. Simultaneously, this drying method helps to obtain a more stable crystal form and reduces the product's moisture absorption.

[0060] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments and comparative examples. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods; the materials and reagents used are commercially available unless otherwise specified.

[0061] Example 1

[0062] A novel process for producing alfacalcidol active pharmaceutical ingredient includes the following steps:

[0063] (1) Catalytic addition reaction: Weigh 100 g of intermediate GHC07, add 920 mL of dichloromethane and 920 mL of ethyl acetate, and stir to dissolve. Add maleic anhydride (1.33 g). Add ZnCl2 (1 mol% of GHC07). Connect the condenser to the argon protection device and stir the reaction at room temperature for 3.5 hours. TLC monitoring showed that the reaction was complete.

[0064] (2) Controlled quenching: The reaction solution was cooled to 15°C. The prescribed amount of triethylamine (approximately 35g) was dissolved in 140g of anhydrous methanol to prepare a 20% dilution. While stirring, this dilution was slowly added dropwise to the reaction solution through a constant-pressure dropping funnel, maintaining the system temperature between 15°C and 20°C at a dropping rate of 1–1.5% of the total volume of the reaction solution per minute (v / v / min). Simultaneously, a pH meter was used to monitor the pH, ensuring the final pH was maintained at 8.5. After the addition was complete, stirring was continued for 10 minutes.

[0065] (3) Post-processing and column chromatography: The reaction solution was concentrated under reduced pressure at 35℃ and 0.09MPa to obtain an oily substance. The subsequent silica gel column chromatography purification steps were the same as the original process, yielding approximately 108g of GHC08 solid.

[0066] (4) Gradient crystallization: The obtained GHC08 solid was added to 700 mL of acetone-ethanol mixed solvent (volume ratio 3:1) and heated to 63 °C with stirring to dissolve. The clear solution was transferred to a crystallization vessel, and the temperature was lowered by a program: at 5 °C / hour to 30 °C and held for 2 hours; then at 2 °C / hour to 0 °C and held for 4 hours; finally, at 3 °C / hour to -15 °C and held for 6 hours. A large amount of crystals precipitated.

[0067] (5) Filtration and drying: The slurry was filtered, and the filter cake was washed twice with 20 mL of acetone pre-cooled to -15°C. The wet filter cake was transferred to a microwave-vacuum drying apparatus, and the temperature was set to 35°C, the vacuum degree to 0.09 MPa, and the microwave power to 300 W (approximately 2.5 W / g based on the material), and dried for 50 minutes. 0.1 g of white crystalline powdered crude alfacalcidol GHC088 was obtained.

[0068] HPLC analysis: HPLC chromatogram Figure 2As shown, the purity was 98.3%, the byproduct 9-acetylanthracene remained at 0.19%, and the calculated yield was 80.1%.

[0069] Example 2

[0070] The steps are basically the same as in Example 1, except that:

[0071] In step (1), the catalyst was changed to ZnCl2 (2 mol% of GHC07), and the reaction time was 3 hours.

[0072] In step (4), the volume ratio of acetone to ethanol is changed to 2:1.

[0073] Step (5) The drying time is changed to 45 minutes.

[0074] Results: 79.1g of product was obtained, with a purity of 97.8%, by-product residue of 0.22%, and a yield of 79.1%.

[0075] Example 3

[0076] The steps are basically the same as in Example 1, except that:

[0077] In step (1), the catalyst was changed to AlCl3 (1 mol% of GHC07), and the reaction time was 2 hours.

[0078] Step (5) The drying time is changed to 45 minutes.

[0079] Results: 78.1g of product was obtained, with a purity of 97.2%, by-product residue of 0.27%, and a yield of 78.1%.

[0080] Comparative Example 1

[0081] The existing production process for alfacalcidol active pharmaceutical ingredient without added catalysts specifically includes the following steps:

[0082] (1) Addition reaction (without catalysis): Weigh 100 g of intermediate GHC07, add 920 mL of dichloromethane and 920 mL of ethyl acetate, place in a single-necked reaction flask, and stir until completely dissolved. Add maleic anhydride (1.33 g) according to the original prescription. Connect a condenser, and connect an argon balloon to the top of the condenser to purge with argon gas for atmosphere protection. At room temperature, turn on magnetic stirring and react for 15 hours. Monitor the reaction progress by TLC.

[0083] (2) Quenching and Post-treatment (One-time addition): After the reaction is complete, the argon gas is turned off. The prescribed amount of triethylamine (approximately 35g) is added to the reaction solution in one go and quickly to quench the reaction. During this process, the temperature of the reaction solution is observed to rise instantaneously to approximately 32°C. After the addition is complete, the mixture is stirred for 10 minutes. The reaction solution is then transferred to a rotary evaporator and concentrated under reduced pressure at a water bath temperature of 30–45°C and a vacuum degree of 0.08–0.1 MPa to obtain a viscous oily substance.

[0084] (3) Column chromatography purification: Column chromatography was performed using a sintered glass funnel (vacuum filtration flask) containing 1400g of silica gel (compacted and lined with filter paper). The silica gel column was first moistened with 4000mL of n-hexane. The oily substance obtained in step (2) was dissolved in an appropriate amount of dichloromethane and anhydrous methanol mixed solvent and then loaded onto the top of the silica gel column for adsorption. The vacuum filtration device was turned on, and the column was first washed with 6.5L of ethyl acetate:n-hexane (volume ratio 1:4) mixed solvent. The eluent was collected and detected by TLC until the residual fluorescence of 9-acetylanthracene disappeared, and this part of the eluent was discarded. Then, elution was performed with 10-30L of ethyl acetate:n-hexane (volume ratio 2:1) mixed solvent. The eluent was detected by TLC, and collection began when the fluorescent spot of intermediate GHC08 appeared, until the fluorescence of TLC detection disappeared. All eluent containing GHC08 was collected. The collected eluent was concentrated under reduced pressure in a rotary evaporator (water bath 30-45℃, vacuum 0.08-0.1MPa) until no liquid droplets fell, yielding GHC08 solid.

[0085] (4) Crystallization (pure solvent, static cooling): Add 700 mL of the prescribed amount of pure acetone (based on the weight of GHC07) to a rotary evaporator containing solid GHC08. Turn on the stirrer and heat the mixture to 60–65 °C in a hot water bath until the solid is completely dissolved, yielding a clear solution. Transfer the hot solution to a 1–2 L single-necked flask and continue stirring for 10 minutes. Then stop heating and allow the reaction solution to cool naturally to below 30 °C with stirring. Stopper the flask with a glass stopper and transfer it to a low-temperature environment, where it will stand at -10 °C for 12–20 hours to crystallize.

[0086] (5) Filtration and Drying (Traditional Vacuum Drying): The crystallized slurry was filtered through a sand core funnel. The filter cake was rinsed with 20 mL of pre-cooled acetone, and filtration continued until no more droplets fell. The wet filter cake was transferred to the drying room and spread evenly on a tray (slightly thinner in the center). The tray was placed in a traditional vacuum drying oven, and the oven door was closed and locked. The vacuum system was turned on, and the drying conditions were set as follows: oven temperature 35±5℃, vacuum degree 0.08~0.1MPa, and continuous drying for 3 hours. After drying, the product was removed, yielding crude alfacalcidol GHC08.

[0087] Unlike Example 1 above, this comparative example did not add any composite catalyst, and other conditions followed the original process. The reaction was stirred for 16 hours to complete. During quenching, the prescribed amount of triethylamine (35g) was rapidly added to the reaction solution in one go, causing the temperature to rise instantly to approximately 32°C and the pH to fluctuate drastically. Crystallization was performed using pure acetone; after dissolution, the solution was placed directly in a -10°C refrigerator and left to stand overnight. Drying was carried out in a standard vacuum drying oven at 35°C for 3 hours.

[0088] The product yielded 62.3g. HPLC analysis showed a purity of 91.8%, with a residual content of 0.48% for the key byproduct 9-acetylanthracene. The yield of this step was 62.3% based on the intermediate GHC07. Observation revealed that the obtained crystals had moderate homogeneity, and the filter cake showed slight caking.

[0089] Comparative Example 2

[0090] Step (1) was the same as in Example 1, using a Lewis acid catalyst, and the reaction was completed in 3.5 hours. Step (2) was quenched using the one-time addition of triethylamine method as in Comparative Example 1. Subsequent steps were the same as in Example 1.

[0091] Results: 77.3g of product was obtained, with a purity of 93.5%, by-product residue of 0.35%, and a yield of 77.3%.

[0092] Analysis: Compared to Comparative Example 1, the use of a catalyst shortened the reaction time and reduced some byproducts. However, the thermal effect of the one-time quenching and the localized high-alkali environment still resulted in lower purity and byproduct indicators compared to Example 1. This indicates that catalysis and controlled quenching technologies have a synergistic effect.

[0093] Comparative Example 3

[0094] Steps (1), (2) and (3) are the same as in Example 1.

[0095] After dissolving in acetone-ethanol (3:1) co-solvent in step (4), instead of using programmed cooling, the mixture was directly stirred and cooled to room temperature, and then placed in a -15°C refrigerator for 12 hours. Subsequent steps were the same as in Example 1.

[0096] Results: During filtration, the filter cake was found to be slightly caking, and the crystals were relatively fine. 77.8g of product was obtained, with a purity of 95.0%, and 0.23% byproduct residue, resulting in a yield of 77.8%.

[0097] Analysis: The co-solvent system is effective in suppressing byproducts, but natural cooling crystallization leads to uneven crystal morphology and size, affecting filtration efficiency and product physical properties, and the purity is also slightly lower than that of Example 1 with gradient crystallization.

[0098] Comparative Example 4

[0099] Steps (1)-(4) are the same as in Example 1.

[0100] Step (5) uses a traditional vacuum drying oven, 35℃, 0.09MPa for 3 hours.

[0101] Results: 78.0 g of product was obtained, with a purity of 96.3%, by-product residue of 0.22%, and a yield of 78.0%. However, the weight gain of the dried product after being placed in a high-humidity environment for 24 hours was approximately 0.5% higher than that of the product in Example 1.

[0102] Analysis: Microwave-vacuum drying, while ensuring purity and yield, has the main advantage of significantly shortening drying time and potentially improving the crystal form and moisture absorption stability of the product.

[0103] Table 4 Summary of production process parameters for each embodiment and comparative example

[0104]

[0105] The specific embodiments of the present invention have been described in detail above, but they are merely examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A novel process for producing alfacalcidol active pharmaceutical ingredient, characterized in that, Includes the following steps: (1) Catalytic addition reaction: In the reaction system of intermediate GHC07 and maleic anhydride, a Lewis acid catalyst is added and the reaction is carried out for 3 to 6 hours under an inert atmosphere. (2) Quenching and post-treatment: The quenching agent is prepared into a diluted solution and added dropwise to the reaction solution in step (1) at a uniform rate. During the dropwise addition, the pH value of the reaction system is monitored and maintained at 8-9, and the temperature of the reaction solution is ≤25℃. After stirring, the solution is concentrated to obtain an oily substance. (3) Column chromatography purification: The oily substance obtained by concentration in step (2) is separated by silica gel column chromatography, the eluent containing the target intermediate GHC08 is collected, and the solid is concentrated. (4) Gradient crystallization: The solid obtained by concentration in step (3) is dissolved in acetone-ethanol co-solvent, heated to dissolve, and then crystallized by programmed gradient cooling. (5) Filtration and drying: The crystallization liquid from step (4) was filtered, the filter cake was rinsed with cold solvent, and then dried in a microwave-vacuum combined drying equipment to obtain crude alfacalcidol GHC08.

2. The new production process according to claim 1, characterized in that, In step (1), the Lewis acid catalyst is selected from at least one of ZnCl2, BF3·Et2O, and AlCl3.

3. The new production process according to claim 2, characterized in that, The amount of the Lewis acid catalyst added is 0.5 to 2% of the weight of the intermediate GHC07.

4. The new production process according to claim 1, characterized in that, In step (2), the quenching agent is triethylamine, and the diluent is a methanol solution of triethylamine with a concentration of 15-25% (w / w).

5. The new production process according to claim 1, characterized in that, In step (4), the volume ratio of acetone to ethanol in the acetone-ethanol co-solvent is 2:1 to 4:

1.

6. The new production process according to claim 5, characterized in that, The volume ratio of acetone to ethanol is 3:

1.

7. The new production process according to claim 1, characterized in that, In step (4), the programmed gradient cooling method includes: First, cool down to 25-35°C at a rate of 3-7°C / hour, and hold for 1-3 hours; Then cool down to -2 to 2°C at a rate of 1 to 3°C / hour, and keep warm for 3 to 5 hours; Finally, cool down to -20 to -10°C at a rate of 2 to 4°C / hour and hold for 5 to 7 hours.

8. The new production process according to claim 1, characterized in that, In step (5), the conditions for microwave-vacuum combined drying are: drying temperature 30-40℃, vacuum degree 0.08-0.1MPa, microwave power density 1-3W / g, and drying time 40-60 minutes.

9. The new production process according to claim 1, characterized in that, In step (5), the cold solvent used for rinsing is acetone or an acetone-ethanol mixture pre-cooled to below -15°C.

10. The new production process according to claim 1, characterized in that, The method also includes further purification of the crude alfacalcidol GHC08 obtained in step (5) to obtain high-purity alfacalcidol.

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