Synthesis method of hydroxymethylenediphosphonic acid disodium salt
By employing steps of sodium hypochlorite substitution, sodium sulfite dehalogenation, acidic hydrolysis, and pyridine salt formation, combined with recrystallization, the safety and yield issues in the synthesis of disodium hydroxymethylene diphosphonate salt were resolved, achieving feasibility for industrial production and improving product purity.
Patent Information
- Application Number
- CN202511632232.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-10
- Publication Date
- 2026-02-24
AI Technical Summary
In the existing technology, the synthesis method of disodium hydroxymethylene diphosphonate has problems such as high reaction risk, low yield and difficulty in product separation, making it difficult to be applied to industrial production.
Disodium hydroxymethylene diphosphonate was prepared by a chemical reaction under mild conditions, using steps of sodium hypochlorite substitution, sodium sulfite dehalogenation, acid hydrolysis, and pyridine salt formation, combined with a recrystallization process.
This invention provides a synthesis method that is safe, has high yield, and is environmentally friendly, suitable for industrial production, improves product purity and stability, and reduces safety risks and energy consumption.
Smart Images
Figure CN121554504A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of radiopharmaceutical technology, and more particularly to radiopharmaceutical chemistry, clinical applications, and medicine, specifically a bone imaging technique. 99m A method for synthesizing the Tc-HDP precursor, disodium hydroxymethylene diphosphonate. Background Technology
[0002] 99m Since its introduction in the 1970s, Tc-HDP has become one of the most essential radiopharmaceuticals in bone scintigraphy. Its primary uses are to detect abnormal metabolic activity in the skeletal system, such as: bone metastases from tumors like breast, prostate, and lung cancer; primary bone tumors; fractures (especially stress and occult fractures); infections like osteomyelitis; metabolic bone diseases; and loosening or infection of joint prostheses. 99m Tc-HDP, with its excellent pharmacokinetic properties—extremely high bone uptake and rapid blood clearance—can obtain high-contrast bone images. It possesses irreplaceable high sensitivity for early screening of bone metastases from malignant tumors, and is also a core tool in diagnosing occult fractures, osteomyelitis, and metabolic bone diseases. Despite challenges from newer technologies such as PET / CT, its cost-effectiveness and ability to perform whole-body imaging remain significant advantages. 99m Tc-HDP remains the first-line choice for the diagnosis of clinical bone diseases.
[0003] Disodium hydroxymethylene diphosphonate is synthesized 99m The precursor of Tc-HDP has very few reported synthetic methods. The main method is described in a 1957 paper published by Procter & Gamble (Quimby et al., Tetrasodium Carbonyldiphosphonate. Synthesis, Reactions, and Spectral Properties (1967) 4111-4114). The specific reaction equation is as follows: This route involves high-temperature esterification followed by conversion to carbonyl groups via sodium hydroxide, followed by high-pressure hydrogen reduction using Raney Ni to obtain the product. However, this process is highly hazardous and yields low results. The sodium hypochlorite in this route is a mixture of monochloro and dichloro compounds after substitution. After hydrolysis and sodium hydroxide substitution, a mixture is obtained. The separation of the products is extremely difficult and the yield is very low. Summary of the Invention
[0004] This invention overcomes the shortcomings of the prior art and provides a stable, reliable synthesis method with mild reaction conditions suitable for industrial production.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The present invention provides a method for synthesizing disodium hydroxymethylene diphosphonate, and the synthetic route is as follows: Includes the following steps: S1. Tetraisopropyl methylene diphosphate was subjected to a substitution reaction in sodium hypochlorite solution, followed by extraction, washing and concentration with organic solvent to obtain tetraisopropyl dichloromethylene diphosphate (intermediate 1). S2. Tetraisopropyl dichloromethylene diphosphate was dehalogenated in sodium sulfite solution, and then extracted, washed and concentrated with organic solvent to obtain tetraisopropyl monochloromethylene diphosphate (intermediate 2). S3. The tetraisopropyl monochloromethylene diphosphate was hydrolyzed under acidic conditions, concentrated, reacted with an organic base to form a salt, and recrystallized to obtain pyridine monochloromethylene diphosphonate (intermediate 3). S4. The monochloromethylene diphosphonate pyridine salt is subjected to a substitution reaction with an alkaline solution, the pH value is adjusted, crystallization and recrystallization are performed to obtain disodium hydroxymethylene diphosphonate.
[0006] In a preferred embodiment of the present invention, in step S1, the mass concentration of the sodium hypochlorite solution is 3-8%, the dropwise addition time of the sodium hypochlorite solution is 0.5-1 h, the temperature of the substitution reaction is 0-10 ℃, and the reaction time is 1-3 h.
[0007] In a preferred embodiment of the present invention, in step S1, the organic solvent is one of n-hexane, n-heptane, or cyclohexane.
[0008] In a preferred embodiment of the present invention, in step S2, the sodium sulfite solution is added dropwise over a period of 1-2 h; the dehalogenation reaction is carried out at a temperature of 0-20 °C for a reaction time of 2-5 h.
[0009] In a preferred embodiment of the present invention, in step S2, the organic solvent is one of dichloromethane, trichloromethane, or 1,2-dichloroethane.
[0010] In a preferred embodiment of the present invention, in step S3, the acidic condition is concentrated hydrochloric acid, the mass-to-volume ratio of tetraisopropyl monochloromethylene diphosphate to concentrated hydrochloric acid is 1 g: 2-3 mL, the hydrolysis reaction temperature is 100-120 °C, and the reaction time is 12-24 h.
[0011] In a preferred embodiment of the present invention, in step S3, the organic base is pyridine; after salt formation, it is recrystallized in a methanol / water mixture, wherein the volume ratio of methanol to water is 2-4:1-2, the recrystallization temperature is 50-70 °C, and the stirring time is 1-2 h.
[0012] In a preferred embodiment of the present invention, in step S4, the alkaline solution is an aqueous solution of sodium hydroxide or potassium hydroxide with a concentration of 2.5-4 mol / L; the temperature of the substitution reaction is 120-150 °C, and the reaction time is 12-24 h.
[0013] In a preferred embodiment of the present invention, in step S4, the pH value is adjusted to 3-4 using 6-8 mol / L hydrochloric acid; recrystallization is carried out in a methanol / water mixture, wherein the volume ratio of methanol to the reaction solution is 2-4:1, the dropping temperature is 70-80 ℃, the crystallization temperature is 0-10 ℃, and the stirring time is 1-2 h.
[0014] In a preferred embodiment of the present invention, in step S4, the recrystallized solid is vacuum dried at 40-50 °C for 6-12 h.
[0015] This invention addresses the shortcomings of the prior art and has the following beneficial effects: (1) This invention provides a method for synthesizing disodium hydroxymethylene diphosphonate. The raw materials and reagents used in this invention are widely available, inexpensive and readily available, and do not contain highly hazardous or toxic chemicals. The process is environmentally friendly, in line with the development direction of green chemistry, and has good prospects for industrial application.
[0016] (2) The reaction conditions of the synthesis process in this invention are mild and controllable, and the reaction temperature is within the conventional operating range. There is no need for extreme high temperature or deep cold conditions, which significantly reduces equipment requirements and energy consumption, and improves the operability and safety of the process.
[0017] (3) In this invention, by forming a salt of monochloromethylene diphosphonic acid with pyridine and recrystallizing it, the intermediate is effectively purified, the chemical purity and crystal form consistency of the product are improved, and a high-quality precursor is provided for subsequent steps, which helps to ensure the efficacy and stability of the final product.
[0018] (4) In the key substitution step of this invention, an alkaline aqueous solution is used to react in a high-pressure reactor, avoiding the use of dangerous materials such as Raney Ni catalyst and high-pressure hydrogen in traditional processes, which greatly reduces safety risks and operational complexity, and is more suitable for large-scale production. Attached Figure Description
[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Figure 1 This is the 1H NMR spectrum of tetraisopropyl dichloromethylene diphosphate from Example 1 of the present invention; Figure 2 This is the 1H NMR spectrum of tetraisopropyl monochloromethylene diphosphate from Example 1 of the present invention; Figure 3 This is the 1H NMR spectrum of the monochloromethylene diphosphonate pyridinium salt of Example 1 of the present invention; Figure 4 This is the 1H NMR spectrum of disodium hydroxymethylene diphosphonate of Example 1 of the present invention; Figure 5 This is the NMR phosphorus spectrum of disodium hydroxymethylene diphosphonate of Example 1 of the present invention. Detailed Implementation
[0020] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0021] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein. Therefore, the scope of protection of the invention is not limited to the specific embodiments disclosed below.
[0022] It should be noted that the raw materials, equipment and reagents used in this invention can all be purchased from the market or obtained through existing preparation methods.
[0023] A method for synthesizing disodium hydroxymethylene diphosphonate includes the following steps: S1. Tetraisopropyl methylene diphosphate was subjected to a substitution reaction in sodium hypochlorite solution, followed by extraction, washing and concentration with organic solvent to obtain tetraisopropyl dichloromethylene diphosphate (intermediate 1). S2. Tetraisopropyl dichloromethylene diphosphate was dehalogenated in sodium sulfite solution, and then extracted, washed and concentrated with organic solvent to obtain tetraisopropyl monochloromethylene diphosphate (intermediate 2). S3. The tetraisopropyl monochloromethylene diphosphate was hydrolyzed under acidic conditions, concentrated, reacted with an organic base to form a salt, and recrystallized to obtain pyridine monochloromethylene diphosphonate (intermediate 3). S4. The monochloromethylene diphosphonate pyridine salt is subjected to a substitution reaction with an alkaline solution, the pH value is adjusted, crystallization and recrystallization are performed to obtain disodium hydroxymethylene diphosphonate.
[0024] In some specific embodiments, in step S1, the mass concentration of the sodium hypochlorite solution is 3-8%, the dropwise addition time of the sodium hypochlorite solution is 0.5-1 h, the temperature of the substitution reaction is 0-10 ℃, and the reaction time is 1-3 h.
[0025] In some specific embodiments, in step S1, the organic solvent is one of n-hexane, n-heptane, or cyclohexane.
[0026] In some specific embodiments, in step S2, the sodium sulfite solution is added dropwise over a period of 1-2 hours; the dehalogenation reaction is carried out at a temperature of 0-20 °C for a reaction time of 2-5 hours.
[0027] In some specific embodiments, in step S2, the organic solvent is one of dichloromethane, trichloromethane, or 1,2-dichloroethane.
[0028] In some specific embodiments, in step S3, the acidic condition is concentrated hydrochloric acid, and the mass-to-volume ratio of tetraisopropyl monochloromethylene diphosphate to concentrated hydrochloric acid is 1 g: 2-3 mL; the hydrolysis reaction temperature is 100-120 ℃, and the reaction time is 12-24 h.
[0029] In some specific embodiments, in step S3, the organic base is pyridine; after salt formation, it is recrystallized in a methanol / water mixture, wherein the volume ratio of methanol to water is 2-4:1-2, the recrystallization temperature is 50-70 °C, and the stirring time is 1-2 h.
[0030] In some specific embodiments, in step S4, the alkaline solution is an aqueous solution of sodium hydroxide or potassium hydroxide with a concentration of 2.5-4 mol / L; the temperature of the substitution reaction is 120-150 °C, and the reaction time is 12-24 h.
[0031] In some specific embodiments, in step S4, the pH value is adjusted to 3-4 using 6-8 mol / L hydrochloric acid; recrystallization is carried out in a methanol / water mixture, wherein the volume ratio of methanol to the reaction solution is 2-4:1, the dropping temperature is 70-80 ℃, the crystallization temperature is 0-10 ℃, and the stirring time is 1-2 h.
[0032] In some specific embodiments, in step S4, the recrystallized solid is vacuum dried at 40-50 °C for 6-12 h.
[0033] To further simplify and make the present invention achieve its objectives and effects, the present invention will be further described in conjunction with the following specific embodiments, but the present invention is not limited to the scope of the embodiments described herein. Example 1
[0034] A method for synthesizing disodium hydroxymethylene diphosphonate, the synthetic route is as follows: Includes the following steps: S1. In a 30 L reactor, 20 kg of 5% sodium hypochlorite aqueous solution was added. After the temperature dropped to 5 ℃, 800 g of tetraisopropyl methylene diphosphate was slowly added dropwise. The reaction temperature was controlled at 5 ℃ and stirred for 2 h. TLC (thin-layer chromatography) showed that the reactants had reacted completely. 3 L*3 of n-hexane was added to the reactor for extraction. The mixture was separated, and the organic phases were combined. 2-3 L of the organic phase was added and dried with 350 g of anhydrous sodium sulfate. The mixture was then filtered. After the filtrate was evaporated to dryness, 950 g of white solid was obtained, which was tetraisopropyl methylene diphosphate diphosphate (intermediate 1), with a yield of 93%. 1 H NMR (CDCl3): δ 4.93 (m,4H),1.33(d,J=6.2 Hz,24H), ( Figure 1 (As shown).
[0035] S2. 580 g of sodium sulfite was dissolved in 20 L of water for later use. In a 30 L reactor, 950 g of tetraisopropyl dichloromethylene diphosphate (intermediate 1) was added. After dissolving in 5 L of ethanol, the reaction temperature was controlled at 10 ℃, and the prepared sodium sulfite aqueous solution was slowly added dropwise. After the addition was complete, the mixture was stirred at 10 ℃ for 3 hours. After the TLC showed that the reactants had reacted completely, 3 L of dichloromethane was added to the reactor for extraction. The mixture was separated, and the organic phases were combined and washed with 2.5 L of purified water. The organic phase was dried with 350 g of anhydrous sodium sulfate and filtered. After evaporating the filtrate, 850 g of colorless oily substance was obtained, which was tetraisopropyl dichloromethylene diphosphate (intermediate 2), with a yield of 95%. 1 H NMR (CDCl3): δ 4.79 (m,4H),3.89 (t,J=16.7 Hz,1H),1.38(d,J=6.1Hz, 24H), ( Figure 2 (As shown).
[0036] In a 5 L reactor (S3), 1.8 L of hydrochloric acid was slowly added to 850 g of tetraisopropyl monochloromethylene diphosphonate (intermediate 2). The mixture was refluxed at 110 °C for 15 h. Under vacuum, the solution was distilled until no liquid flowed out, then 650 mL of ethanol was added. Distillation under vacuum was continued until no liquid flowed out, and this process was repeated three times. Then, 1.15 L of anhydrous ethanol was added to dissolve the solution, and 740 mL of pyridine was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1.5 h. The solution was filtered to obtain 800 g of crude pyridine salt. The crude pyridine salt was added to 750 mL of purified water and heated to 75 °C to dissolve it. Then, 1500 mL of methanol was slowly added dropwise. After the addition was complete, the temperature was lowered to 3 °C and the mixture was stirred for 1.5 h. After the solid was filtered, 500 g of white solid was obtained, which was pyridine monochloromethylene diphosphonate (intermediate 3), with a yield of 77%. 1 H NMR(D2O)δ:8.49(m,2H).8.32 (m,1H),7.82(m,2H),3.74(t,J=16.0 Hz), ( Figure 3 (As shown).
[0037] S4, 420 g of sodium hydroxide was dissolved in 2615 mL of purified water. 500 g of pyridinium monochloromethylene diphosphonate (intermediate 3) was dissolved in the sodium hydroxide solution and then poured into a 3 L autoclave. The mixture was heated to 130 °C and reacted for 18 h. After the reaction was complete, the mixture was cooled to room temperature and the reaction solution was discharged. The pH of the reaction solution was adjusted to 3.5 with 6M hydrochloric acid. The reaction solution was poured into a 30 L reactor and heated to 75 °C. 8.5 L of methanol was slowly added dropwise, and the temperature was lowered to 5 °C. Stirring was continued for 1.5 h. After filtration, a white solid was obtained. The solid was dried in a vacuum drying oven at 45 °C for 8 h to obtain 210 g of white solid, which was disodium hydroxymethylene diphosphonate, with a yield of 58%. 1 H NMR(D2O) δ:3.77(t,J=16.0 Hz), ( Figure 4 (as shown) 31 P NMR (121 MHz, D2O) 614.82 (d. J=16.4Hz), ( Figure 5 (As shown).
[0038] In summary, this invention effectively purifies the intermediate by forming a salt of monochloromethylene diphosphonic acid with pyridine and then recrystallizing it, thereby improving the chemical purity and crystal form consistency of the product. This provides a high-quality precursor for subsequent steps and helps ensure the efficacy and stability of the final product. Furthermore, the raw materials and reagents used are widely available, inexpensive, and free of highly hazardous or toxic chemicals. The process is environmentally friendly, aligns with the development direction of green chemistry, and has promising prospects for industrial application.
[0039] The above description is based on the preferred embodiments of the present invention. It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered exemplary and non-limiting in all respects. The scope of the invention is defined by the appended claims rather than the foregoing description, and all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.
[0040] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
1. A method for synthesizing disodium hydroxymethylene diphosphonate, characterized in that, Includes the following steps: S1. Tetraisopropyl methylene diphosphate was subjected to a substitution reaction in sodium hypochlorite solution, followed by extraction, washing and concentration with organic solvent to obtain tetraisopropyl dichloromethylene diphosphate. S2. Tetraisopropyl dichloromethylene diphosphate was dehalogenated in sodium sulfite solution, and then extracted, washed and concentrated with organic solvent to obtain tetraisopropyl monochloromethylene diphosphate. S3. The tetraisopropyl monochloromethylene diphosphate was hydrolyzed under acidic conditions, concentrated, salted with an organic base, and recrystallized to obtain pyridine monochloromethylene diphosphonate. S4. The monochloromethylene diphosphonate pyridine salt is subjected to a substitution reaction with an alkaline solution, the pH value is adjusted, crystallization and recrystallization are performed to obtain disodium hydroxymethylene diphosphonate.
2. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S1, the mass concentration of the sodium hypochlorite solution is 3-8%, and the dropping time of the sodium hypochlorite solution is 0.5-1 h; the temperature of the substitution reaction is 0-10 ℃, and the reaction time is 1-3 h.
3. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S1, the organic solvent is one of n-hexane, n-heptane, or cyclohexane.
4. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S2, the sodium sulfite solution is added dropwise over a period of 1-2 hours; the dehalogenation reaction is carried out at a temperature of 0-20 °C for a period of 2-5 hours.
5. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S2, the organic solvent is one of dichloromethane, trichloromethane, or 1,2-dichloroethane.
6. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S3, the acidic condition is concentrated hydrochloric acid, and the mass-to-volume ratio of the monochloromethylene diphosphate tetraisopropyl ester to the concentrated hydrochloric acid is 1 g: 2-3 mL; the hydrolysis reaction temperature is 100-120 ℃, and the reaction time is 12-24 h.
7. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S3, the organic base is pyridine; after salt formation, it is recrystallized in a methanol / water mixture, wherein the volume ratio of methanol to water is 2-4:1-2, the recrystallization temperature is 50-70 °C, and the stirring time is 1-2 h.
8. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S4, the alkaline solution is an aqueous solution of sodium hydroxide or potassium hydroxide with a concentration of 2.5-4 mol / L; the temperature of the substitution reaction is 120-150 °C, and the reaction time is 12-24 h.
9. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S4, the pH value is adjusted to 3-4 using 6-8 mol / L hydrochloric acid; recrystallization is carried out in a methanol / water mixture, wherein the volume ratio of methanol to the reaction solution is 2-4:1, the dropping temperature is 70-80 ℃, the crystallization temperature is 0-10 ℃, and the stirring time is 1-2 h.
10. The method for synthesizing disodium hydroxymethylene diphosphonate according to claim 1, characterized in that: In step S4, the recrystallized solid is vacuum dried at 40-50 °C for 6-12 h.