A one-pot process for the preparation of pamidronate disodium

Abstract

This invention relates to a one-pot method for preparing disodium pamidronate. Using β-aminopropionic acid as the starting material, it undergoes a gradient heating reaction with phosphorous acid and phosphorus trichloride under solvent-free conditions. The reaction mixture is then hydrolyzed with dilute hydrochloric acid to obtain pamidronate. The reaction solution is diluted with water, and the pH is adjusted directly with an aqueous sodium hydroxide solution to form a crude disodium pamidronate product. The crude product can be recrystallized in water to obtain high-purity disodium pamidronate. This invention does not use organic solvents, is environmentally friendly, and is simpler to operate. The overall yield is over 80%, the purity reaches over 99.96%, and the production cost is significantly reduced, making it more suitable for industrial-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a one-pot method for preparing disodium pamidronate. Background Technology

[0002] Osteoporosis is a common and prevalent disease worldwide. Since the 1980s, the international medical community has witnessed a surge in osteoporosis research, which has become a rapidly developing field. Bisphosphonates, as bone resorption inhibitors, have a strong affinity for calcium phosphate. The amount required to inhibit hydroxyapatite crystal resorption is much lower than the amount needed to inhibit its formation and growth; therefore, small doses are sufficient to inhibit bone resorption and produce therapeutic effects. Pamidronate disodium is an effective bisphosphonate analog that inhibits bone resorption. Its structure is similar to dihydropyrrolic acid compounds in vivo, but it is not easily broken down by enzymes in vivo. In vivo and animal studies have shown that it strongly inhibits the dissolution of hydroxyapatite (a major component of bone and teeth) and osteoclast activity, exhibiting a very significant inhibitory effect on bone resorption.

[0003] Pamidronate disodium, a second-generation bisphosphonate drug, incorporates an amino group at the end of its carbon chain, significantly enhancing its biological activity. Its inhibitory effect on bone resorption is 100 times stronger than that of first-generation etidronate sodium and 10 times stronger than that of clodronate disodium. It is used to treat hypercalcemia in tumors, multiple myelopathy, and bone metastases from malignant tumors, with remarkable efficacy. After its launch in Argentina in 1987, it was subsequently widely marketed and used in the UK, US, and European countries.

[0004] Pammidronate disodium, chemically named (3-amino-1-hydroxypropylidene)bisphosphonate disodium salt pentahydrate, is a white powder, readily soluble in water and 2N sodium hydroxide, slightly soluble in 0.1N hydrochloric acid and 0.1N acetic acid, and generally insoluble in organic solvents. Its molecular formula is C3H9NO7P2Na2 / 5H2O, with a molecular weight of 369.1, and its structural formula is as follows:

[0005]

[0006] Currently, the main processes for synthesizing disodium pamidronate include solvent extraction and melt extraction. The differences between these processes mainly lie in the reagents used to prepare the acyl chloride or phosphorylation. Both processes involve first preparing free pamidronate, then adding an organic solvent for crystallization, filtration, drying, and finally forming a salt with sodium hydroxide.

[0007]

[0008] Phosphorylation reagents most commonly used are phosphorous acid, while chlorination reagents typically include phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride. These reactions generally produce a viscous substance during preparation. To improve the solubility of the reaction solution, Blum H et al. used methanesulfonic acid as a solvent in their paper "Progress for the production of 3-amino-1-hydroxypropane-1,1-diphosphonicacid." However, this reaction requires low temperatures, is slow, and takes a long time. Furthermore, the post-treatment requires high-temperature evaporation to remove the methanesulfonic acid, which is not conducive to large-scale production.

[0009] In their paper "Substituted alkanediphosphonic acids and pharmaceutical use," Jaeggi KA et al. used chlorobenzene as a solvent. However, a viscous substance was also produced during the reaction. The solvent chlorobenzene and the viscous substance were essentially in a separate layer, failing to improve the mixing effect. Furthermore, chlorobenzene is a highly toxic solvent, and its residue could affect product safety. In addition, existing processes for separating pamidronic acid typically use large amounts of alcohol solvents or acetone crystallization. Methanol can react with the product to form phosphate ester genotoxic impurities, and acetone may react with amino groups in the structure to generate new impurities, both of which can affect product quality.

[0010] The article "Preparation of Pamidronate Disodium" published by Li Peng et al. optimized the existing process: β-aminopropionic acid reacts with 85% phosphoric acid and phosphorus trichloride at 95-100℃, is hydrolyzed with 9 mol / L hydrochloric acid, and crystallized with acetone to obtain pamidronate. The pamidronate disodium is then obtained by salting with sodium hydroxide solution. By adjusting the molar ratio of β-aminopropionic acid to phosphoric acid, the yield increased from 22.0% to 50.8%. However, the preparation of pamidronate uses a large amount of acetone, which easily introduces new impurities, leading to a decrease in product purity. Furthermore, the operation is relatively cumbersome and unsuitable for large-scale production.

[0011] Zhu Chongquan et al. also made reasonable improvements: pamidronate disodium was synthesized by directly reacting β-aminopropionic acid solution with phosphorus trichloride. The synthetic route is as follows:

[0012]

[0013] This route avoids the requirement for anhydrous reagents and solvents by not using anhydrous phosphorous acid. However, the process relies on the direct chlorination and phosphorylation of phosphorus trichloride with β-aminopropionic acid, which can easily lead to excessively rapid local reactions and temperature surges, making the process highly dangerous during scale-up. Furthermore, the process uses chlorobenzene as a solvent, which is highly toxic and cannot be recycled, hindering industrial production.

[0014] In summary, most of the processes reported in the current literature use chlorobenzene (which is highly toxic) as a solvent, adding organic solvents (methanol, acetone) to crystallize, filtering to obtain free pamidronate, drying, and then reacting with sodium hydroxide solution to form a salt to produce disodium pamidronate. Existing processes suffer from drawbacks such as complexity, high cost, difficulty in quality control, serious environmental pollution, and health hazards. Therefore, it is essential to develop a green, environmentally friendly, simple, high-yield, low-cost route suitable for industrial production. Summary of the Invention

[0015] The purpose of this invention is to overcome the defects in the existing technology and provide a green, environmentally friendly, simple, pure, and yield-controllable one-pot preparation process of disodium pamidronate suitable for industrial application.

[0016] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0017] This invention provides a one-pot method for preparing disodium pamidronate, specifically comprising the following steps:

[0018]

[0019] S1 phosphorylation: Under solvent-free conditions, phosphorous acid and phosphorus trichloride are added to β-aminopropionic acid, and the mixture is heated from room temperature to 75±2℃ with stirring. After solidification, stirring is stopped, and the mixture is kept at this temperature for 3 to 8 hours.

[0020] S2 hydrolysis: Add hydrochloric acid solution, heat to 95-100℃, react for 2-3 hours, dilute with purified water, cool to room temperature, and stir for 1.5-2.5 hours;

[0021] S3 salt formation: Add sodium hydroxide solution at room temperature, adjust pH to 7.0-8.0, stir, crystallize, and filter to obtain crude product;

[0022] S4 recrystallization: Add purified water to the crude product, heat to 65-75℃, add activated carbon, stir for 0.5±0.1h, hot filter, and crystallize the filtrate by gradient cooling. Filter and dry to obtain disodium pamidronate.

[0023] As a further improvement of the present invention, the molar ratio of phosphorous acid and phosphorus trichloride to β-aminopropionic acid in step S1 is 1.5-3:1.5-3:1.

[0024] As a further improvement of the present invention, the ratio of phosphorous acid and phosphorus trichloride in step S1 is 1:1.

[0025] As a further improvement of the present invention, the molar ratio of phosphorous acid and phosphorus trichloride to β-aminopropionic acid in step S1 is 2.5∶2.5∶1.

[0026] As a further improvement of the present invention, the specific method for heating from room temperature to 75±2℃ in step S1 is to raise the temperature from room temperature to 45±2℃ at a rate of 0.5℃ / min, keep it warm and stir for 30min, then raise the temperature to 60~65℃ at a rate of 0.25℃ / min, keep it warm and stir for 30min, and finally raise the temperature to 75℃ at a rate of 0.25℃ / min. After solidification, stop stirring and keep it warm for 5h.

[0027] As a further improvement of the present invention, in step S2, the amount of dilute hydrochloric acid added is 135-145g, the concentration is 3-9N, and the amount of purified water added is 1280-430mL.

[0028] As a further improvement of the present invention, in step S3, the concentration of sodium hydroxide solution is 30-50%, and the crystallization time is 5-6 hours.

[0029] As a further improvement of the present invention, the amount of purified water added in step S4 is 2.5 to 5 times the mass of the β-aminopropionic acid.

[0030] As a further improvement of the present invention, the gradient cooling crystallization operation in step S4 is as follows: first, the temperature is lowered to 25±2℃ at a rate of 0.25℃ / min and stirred for 2 hours to crystallize, and then the temperature is lowered to 5±2℃ at a rate of 0.5℃ / min and stirred for 2 hours to crystallize.

[0031] As a further improvement of the present invention, in step S4, the amount of activated carbon added is 6% of the mass of the starting raw material β-aminopropionic acid, and the drying is carried out by vacuum drying at 45±2℃.

[0032] The beneficial effects of adopting the above technical solution are as follows:

[0033] 1. The method provided by this invention does not add highly toxic solvents such as chlorobenzene and methanesulfonic acid in the phosphorylation step, which is a solvent-free green synthesis process. By controlling the reactant feed ratio, the material addition time and temperature, the purity of the product and the reaction yield are improved.

[0034] 2. After the hydrolysis reaction is completed, the product is directly cooled, diluted with water and stirred. Then, sodium hydroxide solution is added to adjust the pH to form a salt. After filtration, crude disodium pamidronate is obtained. The intermediate pamidronate does not need to be separated and dried.

[0035] 3. This invention does not involve any organic solvents throughout the process, which avoids the use of alcohol solvents to generate phosphite genotoxic impurities by reacting with phosphite groups, as well as impurities generated by the reaction of acetone with amino groups in the structure. The product has higher purity, more guaranteed quality, a higher degree of greenness in the process, and less environmental impact.

[0036] 4. The recrystallization process of this invention adopts a gradient crystallization method, which can avoid the phenomenon of impurity encapsulation caused by excessively rapid cooling, resulting in higher product purity and ensuring a high product yield.

[0037] 5. This invention realizes a one-pot method for preparing disodium pamidronate, which is simpler to operate, with a total yield of over 81.5% and a purity of over 99.96%, greatly reducing production costs and making it more suitable for industrial-scale production. Attached Figure Description

[0038] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0039] Figure 1 This is the 1H NMR spectrum of pamidronate disodium obtained in Example 1 of this invention;

[0040] Figure 2 This is the carbon NMR spectrum of disodium pamidronate obtained in Example 1 of this invention;

[0041] Figure 3 This is the NMR phosphorus spectrum of disodium pamidronate obtained in Example 1 of this invention. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described clearly and completely below in conjunction with specific embodiments.

[0043] Example 1

[0044] S1: Add 400.00g (4.50mol) of β-aminopropionic acid, 922.50g (11.25mol) of phosphorous acid and 1.53kg (11.25mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.5℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5h.

[0045] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0046] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0047] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 85.80% and a purity of 99.98%.

[0048] Example 2

[0049] S1: Add 800.00g (9.00mol) of β-aminopropionic acid, 1.10kg (13.50mol) of phosphorous acid and 1.83kg (13.50mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.5℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5h.

[0050] S2: Slowly add 850.00 mL of 9N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 12.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0051] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0052] S4: Add the crude product to 3.00L of purified water, heat to 75℃, add 48.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 82.40% and a purity of 99.97%.

[0053] Example 3

[0054] S1: Add 200.00g (2.25mol) of β-aminopropionic acid, 461.55g (5.63mol) of phosphorous acid and 0.77kg (5.63mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.5℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, and stop stirring. Keep the reaction at this temperature for 8h.

[0055] S2: Slowly add 640.00 mL of 3N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 3.0 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0056] S3: Adjust the pH to 8.0 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0057] S4: Add the crude product to 0.75L of purified water, heat to 75℃, add 12.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 81.72% and a purity of 99.96%.

[0058] Example 4

[0059] S1: Add 400.00 g (4.50 mol) of β-aminopropionic acid, 1.10 kg (13.50 mol) of phosphorous acid and 1.83 kg (13.50 mol) of phosphorus trichloride to a 20 L reactor. Under stirring at room temperature, raise the temperature to 45 °C at a rate of 0.5 °C / min, and keep stirring at this temperature for 30 min. Then raise the temperature to 60 °C at a rate of 0.25 °C / min, and keep stirring at this temperature for 30 min. Finally, raise the temperature to 75 °C at a rate of 0.25 °C / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5 h.

[0060] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0061] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0062] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 82.95% and a purity of 99.97%.

[0063] Comparative Example 1

[0064] S1: Add 400.00g (4.50mol) of β-aminopropionic acid and 922.50g (11.25mol) of phosphorous acid to a 20L reactor, heat to 75℃ at a rate of 0.5℃ / min, then add 1.53kg (11.25mol) of phosphorus trichloride, and stop stirring when it becomes impossible to stir. Keep the reaction at this temperature for 5 hours.

[0065] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0066] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0067] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 75.60% and a purity of 99.89%.

[0068] Comparative Example 2

[0069] S1: Add 400.00g (4.50mol) of β-aminopropionic acid, 922.50g (11.25mol) of phosphorous acid and 1.53kg (11.25mol) of phosphorus trichloride to a 20L reactor. While stirring at room temperature, raise the temperature to 55℃ at a rate of 0.5℃ / min, keep stirring at this temperature for 30min, and then raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed. Stop stirring and keep the reaction at this temperature for 5h.

[0070] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0071] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0072] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 77.53% and a purity of 99.91%.

[0073] Comparative Example 3

[0074] S1: Add 400.00g (4.50mol) of β-aminopropionic acid, 922.50g (11.25mol) of phosphorous acid and 1.53kg (11.25mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5h.

[0075] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0076] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0077] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 79.85% and a purity of 99.93%.

[0078] Comparative Example 4

[0079] S1: Add 400.00g (4.50mol) of β-aminopropionic acid and 922.50g (11.25mol) of phosphorous acid to a 20L reactor, heat to 75℃ at a rate of 0.25℃ / min, then add 1.53kg (11.25mol) of phosphorus trichloride, and stop stirring when it becomes impossible to stir. Keep the reaction at this temperature for 5 hours.

[0080] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0081] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0082] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 74.30% and a purity of 99.91%.

[0083] Comparative Example 5

[0084] S1: Add 400.00g (4.50mol) of β-aminopropionic acid, 922.50g (11.25mol) of phosphorous acid and 0.37kg (2.70mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.5℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5h.

[0085] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0086] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0087] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 75.45% and a purity of 99.90%.

[0088] Comparative Example 6

[0089] S1: Add 400.00 g (4.50 mol) of β-aminopropionic acid, 1.29 kg (15.75 mol) of phosphorous acid and 2.14 kg (15.75 mol) of phosphorus trichloride to a 20 L reactor. Under stirring at room temperature, raise the temperature to 45 °C at a rate of 0.5 °C / min, and keep stirring at this temperature for 30 min. Then raise the temperature to 60 °C at a rate of 0.25 °C / min, and keep stirring at this temperature for 30 min. Finally, raise the temperature to 75 °C at a rate of 0.25 °C / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5 h.

[0090] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0091] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0092] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 75.62% and a purity of 99.92%.

[0093] Comparative Example 7

[0094] S1: Add 400.00g (4.50mol) of β-aminopropionic acid, 922.50g (11.25mol) of phosphorous acid and 1.53kg (11.25mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.5℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5h.

[0095] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0096] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0097] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 5℃ at a rate of 0.5℃ / min and stir to precipitate crystals for 4h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 72.10% and a purity of 99.91%.

[0098] Comparative Example 8

[0099] S1: Add 400.00g (4.50mol) of β-aminopropionic acid, 922.50g (11.25mol) of phosphorous acid and 1.53kg (11.25mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.5℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5h.

[0100] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0101] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0102] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.5℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 74.45% and a purity of 99.91%.

[0103] Comparative Example 9

[0104] S1: Add 400.00g (4.50mol) of β-aminopropionic acid, 922.50g (11.25mol) of phosphorous acid and 1.53kg (11.25mol) of phosphorus trichloride to a 20L reactor. Under stirring at room temperature, raise the temperature to 45℃ at a rate of 0.5℃ / min, and keep stirring at this temperature for 30min. Then raise the temperature to 60℃ at a rate of 0.25℃ / min, and keep stirring at this temperature for 30min. Finally, raise the temperature to 75℃ at a rate of 0.25℃ / min until stirring can no longer be performed, then stop stirring and keep the reaction at this temperature for 5h.

[0105] S2: Slowly add 640.00 mL of 6N hydrochloric acid, start stirring and heat to 100°C, maintain the temperature for 2.5 h. Cool the filtrate to 75°C, slowly add 6.00 L of purified water, and maintain the temperature at 25°C with stirring for 2 h after the addition is complete;

[0106] S3: Adjust the pH to 7.5 with 40% sodium hydroxide solution, while controlling the temperature at 20℃. After adjustment, stir and crystallize for 6 hours, then filter to obtain crude pamidronate disodium product.

[0107] S4: Add the crude product to 1.50L of purified water, heat to 75℃, add 24.00g of pharmaceutical charcoal, stir and decolorize for 0.5h, filter while hot, cool the filtrate to 25℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, then cool to 5℃ at a rate of 0.25℃ / min and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 45℃ to obtain the target compound, disodium pamidronate, with a yield of 77.83% and a purity of 99.92%.

[0108] The yields and purities of the products from Examples 1-4 and Comparative Examples 1-9 were recorded and statistically analyzed, and the results are as follows:

[0109]

[0110]

[0111] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A one-pot method for preparing disodium pamidronate, characterized in that, Specifically, the steps include the following: ； S1 phosphorylation: Under solvent-free conditions, phosphorous acid and phosphorus trichloride are added to β-aminopropionic acid, and the mixture is heated from room temperature to 75±2℃ with stirring. After solidification, stirring is stopped, and the mixture is kept at this temperature for 3 to 8 hours. S2 hydrolysis: Add hydrochloric acid solution, heat to 95-100℃, react for 2-3 hours, dilute with purified water, cool to room temperature, and stir for 1.5-2.5 hours; S3 salt formation: Add sodium hydroxide solution at room temperature, adjust pH to 7.0-8.0, stir, crystallize, and filter to obtain crude product; S4 recrystallization: Add purified water to the crude product, heat to 65-75℃, add activated carbon, stir for 0.5±0.1h, hot filter, the filtrate is subjected to gradient cooling to crystallize, filtered, and dried to obtain disodium pamidronate. The specific method for heating from room temperature to 75±2℃ in step S1 is to raise the temperature from room temperature to 45±2℃ at a rate of 0.5℃ / min, keep it warm and stir for 30min, then raise the temperature to 60~65℃ at a rate of 0.25℃ / min, keep it warm and stir for 30min, and finally raise the temperature to 75℃ at a rate of 0.25℃ / min. After solidification, stop stirring and keep it warm for 5h. The gradient cooling crystallization operation in step S4 is as follows: first, the temperature is lowered to 25±2℃ at a rate of 0.25℃ / min and stirred for 2 hours to crystallize, and then the temperature is lowered to 5±2℃ at a rate of 0.5℃ / min and stirred for 2 hours to crystallize.

2. The method for preparing disodium pamidronate in a one-pot process according to claim 1, characterized in that, In step S1, the molar ratio of phosphorous acid and phosphorus trichloride to β-aminopropionic acid is 1.5–3:1.5–3:

1.

3. The method for preparing disodium pamidronate in a one-pot process according to claim 1, characterized in that, In step S1, the ratio of phosphorous acid to phosphorus trichloride is 1:

1.

4. The method for preparing disodium pamidronate in a one-pot process according to claim 1, characterized in that, In step S1, the molar ratio of phosphorous acid and phosphorus trichloride to β-aminopropionic acid is 2.5:2.5:

1.

5. The method for preparing disodium pamidronate in a one-pot process according to claim 1, characterized in that, The concentration of the hydrochloric acid solution in step S2 is 3-9N.

6. The method for preparing disodium pamidronate in a one-pot process according to claim 1, characterized in that, In step S3, the concentration of sodium hydroxide solution is 30-50%, and the crystallization time is 5-6 hours.

7. The method for preparing disodium pamidronate in a one-pot process according to claim 1, characterized in that, In step S4, the amount of purified water added is 2.5 to 5 times the mass of the β-aminopropionic acid.

8. The method for preparing disodium pamidronate in a one-pot process according to claim 1, characterized in that, In step S4, the amount of activated carbon added is 6% of the mass of the starting material β-aminopropionic acid, and the drying is carried out under vacuum at 45±2℃.

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